WO2011033099A1 - Alkene oxindole derivatives and their uses to treat obesity, diabetes and hyperlipidemia - Google Patents

Alkene oxindole derivatives and their uses to treat obesity, diabetes and hyperlipidemia Download PDF

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WO2011033099A1
WO2011033099A1 PCT/EP2010/063770 EP2010063770W WO2011033099A1 WO 2011033099 A1 WO2011033099 A1 WO 2011033099A1 EP 2010063770 W EP2010063770 W EP 2010063770W WO 2011033099 A1 WO2011033099 A1 WO 2011033099A1
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phenyl
indol
dihydro
ylidene
oxo
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PCT/EP2010/063770
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French (fr)
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Li Chen
Lichun Feng
Mengwei Huang
Jia Li
Fajun Nan
Tao Pang
Lifang Yu
Mei Zhang
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F. Hoffmann-La Roche Ag
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Priority to CN2010800418192A priority Critical patent/CN102666485A/en
Priority to BR112012006172A priority patent/BR112012006172A2/en
Priority to MX2012002477A priority patent/MX2012002477A/en
Priority to IN765DEN2012 priority patent/IN2012DN00765A/en
Priority to JP2012530228A priority patent/JP2013505281A/en
Priority to AU2010297252A priority patent/AU2010297252A1/en
Priority to CA2772674A priority patent/CA2772674A1/en
Priority to EP10757407A priority patent/EP2480530A1/en
Publication of WO2011033099A1 publication Critical patent/WO2011033099A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

A compound of formula (I) as well as pharmaceutically acceptable salt thereof, wherein R1 to R7 have the significance given in claim 1, can be used as a medicament.

Description

ALKENE OXINDOLE DERIVATIVES AND THEIR USES TO TREAT OBESITY, DIABETES AND HYPERLIPIDEMIA
The invention relates to compounds which are activators of AMP-activated protein kinase (AMPK) and which are useful in the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
The invention relates in particular to a compound of formula (I)
Figure imgf000002_0001
wherein
R1 is hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy or alkylcarbonyl;
R2 is hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy or alkylcarbonyl;
R3 is hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy or alkylcarbonyl;
R4 is hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy or alkylcarbonyl;
R5 is is alkyl, hydroxyalkyl, cycloalkyl, phenylalkyl, halophenylalkyl, phenyl,
substituted phenyl, thiophenyl or pyridinyl, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl;
R6 is is alkyl, hydroxyalkyl, cycloalkyl, phenylalkyl, halophenylalkyl, phenyl,
substituted phenyl, thiophenyl or pyridinyl, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; provided that R5 and R6 are not both methoxyphenyl at the same time;
R7 is substituted phenyl, pyridinyl, substituted pyridinyl, thiazolyl, substituted
thiazolyl or carboxy, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, wherein substituted pyridinyl and substituted thiazolyl are pyridinyl and thiazolyl substituted with alkoxycarbonyl or carboxy; and provided that when one of R5 and R6 is phenyl and the other one is phenyl,
methylphenyl or alkoxyphenyl, then R7 is alkoxycarbonylphenyl; n is 0 or 1; or a pharmaceutically acceptable salt or ester thereof.
The invention also relates to a process for the manufacture of these novel compounds and medicaments containing them. The compounds of the invention have activation effect on AMP (adenosine monophosphate) -activated protein kinase, which results in lowered blood glucose. The invention thus also concerns the use of such compounds for the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
Obesity and type 2 diabetes, hypertension and cardiovascular disease, are diseases that feature serious disturbances in glucose and lipid metabolism that severely affect the health and quality of life of affected individuals. The increasing prevalence of these diseases makes finding new drug targets for treating this syndrome an urgent task.
AMP-activated protein kinase acts as a cellular energy sensor and regulator. It is activated by an increase in the cellular AMP:ATP ratio induced by metabolic stress. Once activated, AMPK switches on catabolic pathways that generate ATP and switches off ATP- consuming anabolic pathways by acute regulation of the activity of key enzymes in metabolism and chronic regulation of the expression of pivotal transcription factors (Hardie, DG. Nature reviews 8 (2007b), 774-785; Woods, A et al. Molecular and cellular biology 20 (2000), 6704-6711). The growing evidence of AMPK regulatory effects on glucose and lipid metabolism makes it a potential drug target for treatment of diabetes and metabolic syndrome (Carling, D. Trends Biochem Sci 29(2004), 18-24; Hardie, DG.
Annual review of pharmacology and toxicology 47 (2007a), 185-210; Kahn, BB et al. Cell metabolism 1 (2005), 15-25; Long, YC et al. The Journal of clinical investigation 116 (2006), 1776-1783). At the physiological level, this concept has been supported by two adipokines, leptin and adiponectin, both of which exert excellent effects on glucose and lipid metabolism (Friedman, JM and Halaas, JL. Nature 395 (1998), 763-770; Muoio, DM et al. Diabetes 46 (1997), 1360-1363; Yamauchi, T et al. Nature medicine 7 (2001), 941-946). Recent studies suggest that leptin and adiponectin exert their antidiabetic effects by activating AMPK. Leptin stimulates muscle fatty acid oxidation by activating AMPK directly and through a hypothalamic-adrenergic pathway (Minokoshi, Y et al. Nature 415 (2002), 339-343). Adiponectin stimulates glucose uptake and fatty acid oxidation in vitro by activation of AMPK. Furthermore, it exerts its hypoglycemic effect by decreasing PEPCK and G6Pase expression, whereas the administration of dominant negative al adenovirus reverses the effect in vivo (Yamauchi, T et al. Nature medicine 8 (2002), 1288-1295).
At the pharmacological level, the concept of AMPK as a potential target for treating metabolic syndrome has been further supported by the discovery of two major classes of existing antidiabetic drugs: thiazolidinediones (rosiglitazone, troglitazone and
pioglitazone) and biguanides (metformin and phenformin) activate AMPK in cultured cells and in vivo. Rosiglitazone is traditionally considered to be a PPARy agonist and exerts its antidiabetic effects through differentiation of adipocytes (Semple, RK et al. The Journal of clinical investigation 116 (2006), 581-589). Recent findings indicate that AMPK may be involved in the antidiabetic effects of rosiglitazone (Brunmair, B et al. The Journal of biological chemistry 277 (2002), 25226-25232; Kadowaki, T et al. The Journal of clinical investigation 116(2006), 1784-1792). In the case of metformin, an existing antidiabetic agent without a defined mechanism of action, recent studies demonstrate that it could activate AMPK in vitro and in vivo by inhibiting complex I (El-Mir, MY et al. The Journal of biological chemistry 275 (2000), 223-228; Owen, MR et al. The Biochemical journal 348 Pt 3 (2000), 607-614; Zhou, G et al. The Journal of clinical investigation 108 (2001), 1167- 1174), and the hypoglycemic effect could be blocked completely by knockout of its upstream kinase LKB1, confirming the key role of AMPK in mediating the antidiabetic effect of metformin (Shaw, RJ et al. Science (New York) N.Y. 310 (2005), 1642-1646). Most recently, Cool and coworkers have identified a small direct AMPK activator, A- 769662, which exerts antidiabetic effects in vivo (Cool, B et al. Cell metabolism 3 (2006), 403-416). Jia Li's laboratory has identified a small AMPK activator, PTl, which activates the inactive forms of AMPK a2398 and al394 with micromolar activity and exerts some cellular effects (Pang, T et al. The Journal of biological chemistry 283 (2008), 16051- 16060).
It has been found that the compounds of the present invention are potent AMPK activators. The compounds of the invention are therefore useful in the treatment or prophylaxis ofdiseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
As used herein, the term "alkyl" alone or in combination signifies a saturated, linear - or branched chain alkyl group containing 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl and tert-butyl. Preferred "alkyl" groups are methyl, ethyl, isopropyl and tert-butyl. The term "alkoxy" alone or in combination signifies a group alkyl-O-, wherein the
"alkyl" is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy and t-butoxy. Preferred alkoxy groups are methoxy and ethoxy and more preferably methoxy.
The term "cycloalkyl" alone or in combination refers to a saturated carbon ring containing from 3 to 7 carbon atoms, preferably from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A preferred cycloalkyl group is cyclohexyl.
The term "halogen" means fluorine, chlorine, bromine or iodine. Halogen is preferably fluorine or chlorine. The term "carboxy" alone or in combination refers to the group -COOH.
The term "carbonyl" alone or in combination refers to the group -C(O)-.
The term "amino" alone or in combination refers to primary (-NH2-), secondary (- NH-) or tertiary amino (-N-).
The term "alkylsulfanyl" alone or in combination refers to the group -S-alkyl.
The term "sulfonyl" alone or in combination refers to the group -S(0)2- The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, fiowability and solubility of compounds. It is for example described in Bastin R.J., et. al., Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et. al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferred are the sodium salts of the compounds of formula (I).
"Pharmaceutically acceptable esters" means that compounds of formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include
physiologically acceptable and metabolically labile ester derivatives, such as
methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters.
Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention. Preferred are the methyl and ethyl esters of the compounds of formula (I).
Preferred is a compound according of formula (I) wherein R1 is hydrogen, halogen or alkoxy. Further preferred is a compound of formula (I) wherein R1 is hydrogen, fiuoro or chloro.
Still further preferred is a compound of formula (I) wherein R1 is hydrogen.
A compound of formula (I) wherein R2 is hydrogen, halogen or alkoxy is preferred.
Also preferred is a compound of formula (I) wherein R2 is hydrogen or fiuoro. Also particularly preferred is a compound of formula (I) wherein R3 is hydrogen, halogen or alkoxy.
A compound of formula (I) wherein R3 is hydrogen, fluoro, chloro or methoxy is also preferred.
In particular, preferred is a compound of formula (I) wherein R3 is hydrogen.
Furthermore, preferred is a compound of formula (I) wherein R4 is hydrogen, halogen or alkoxy.
A compound of formula (I) wherein R4 is hydrogen or fluoro is preferred.
A compound of formula (I) wherein R5 is alkyl, halophenylalkyl, phenyl, substituted phenyl, thiophenyl or pyridinyl, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl is further preferred.
In particular, preferred is a compound of formula (I) wherein R5 is phenyl, chlorophenyl, methoxyphenyl, methylphenyl, cyanophenyl, trifluoromethylphenyl, chlorofluorophenyl, trimethoxyphenyl, difluorophenyl, dichlorophenyl, bromophenyl, chlorotrifluoromethylphenyl, methylsulfanylphenyl, aminosulfonylphenyl,
methylsulfonylphenyl, thiophenyl, fluorophenyl, pyridinyl, bis(trifluoromethyl)phenyl, isopropylphenyl, neopentyl, isopentyl, methylcarbonylphenyl or tert-butyl.
Also preferred is a compound of formula (I) wherein R5 is halophenyl or
cyanophenyl.
A compound of formula (I) wherein R5 is chlorophenyl or cyanophenyl is also preferred.
Furthermore, preferred is a compound of formula (I) wherein R6 is alkyl, hydroxyalkyl, cycloalkyl, phenyl or halophenyl.
Moreover, a compound of formula (I) wherein R6 is alkyl or phenyl is also preferred.
Further, a compound of formula (I) wherein R6 is isopropyl or phenyl is also preferred.
In particular, preferred is a compound of formula (I) wherein R6 is methyl, phenyl, methoxyphenyl, chlorophenyl, neopentyl, isopropyl, cyclohexyl, hydroxypropyl or tert- butyl. Particularly preferred is a compound of formula (I) wherein R7 is substituted phenyl, substituted pyridinyl, substituted thiazolyl or carboxy, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, wherein substituted pyridinyl and substituted thiazolyl are pyridinyl and thiazolyl substituted with alkoxycarbonyl or carboxy.
Also particularly preferred is a compound of formula (I) wherein R7 is
carboxyphenyl, alkoxycarbonylphenyl or carboxypyridinyl.
A compound according of formula (I) wherein R7 is carboxyphenyl,
methoxycarbonylphenyl or carboxypyridinyl is further preferred.
Further preferred is a compound of formula (I) wherein R7 is ethoxycarbonylphenyl, methoxycarbonylmethylphenyl, phenyl substituted with methyl and methoxycarbonyl, carboxy, methoxycarbonylphenyl, ethoxycarbonylmethoxyphenyl,
isopropylaminocarbonylphenyl, methoxycarbonylpyridinyl, ethoxycarbonylthiazolyl, methoxyphenyl, trihydroxyphenyl, hydroxyphenyl, carboxyphenyl,
carboxymethoxyphenyl, carboxythiazolyl, carboxypyridinyl or
methylsulfonylminocarbonylphenyl.
Also preferred is a compound of formula (I) wherein n is 1.
Particularly preferred is a compound of formula (I) selected from
3-{2-Oxo-3-[l-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-l-yl}-benzoic acid ethyl ester;
(3-{2-Oxo-3-[l-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-l-yl}-phenyl)-acetic acid methyl ester;
2- Methyl-5-{2-oxo-3-[l-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-l-yl}-benzoic acid methyl ester;
[2-Oxo-3-(l-phenyl-ethylidene)-2, 3 -dihydro-indol-l-yl] -acetic acid;
3- {3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-7-fiuoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-(3-Benzhydrylidene-2-oxo-2,3-dihydro-indol-l-ylmethyl)-benzoic acid methyl ester; 3-{3-[l-(4-Methoxy-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{2-Oxo-3-[l-phenyl-l-p-tolyl-meth-(E)-ylidene]-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Cyano-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{2-Oxo-3-[l -phenyl- l-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3 -{3 - [ 1 -(3 -Chloro-4-fluoro-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 -dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[l-phenyl-l-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol- l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(3,4-Difluoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(3-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(2-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(3,5-Dichloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3- {3-[l-(2,3-Dichloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
4- {3 - [ 1 -(4-Chloro-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 -dihydro-indol- 1 - ylmethylj-benzoic acid methyl ester; 3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(2-Bromo-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(2-Chloro-5-trifluoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene] -2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(3-Bromo-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(2-Methylsulfanyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-ind( l-ylmethyl}-benzoic acid methyl ester;
3-{7-Chloro-3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[l-phenyl-l-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[l-phenyl-l-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(2-Methanesulfonyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[l-phenyl-l-thiophen-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene] -2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester; (4-{3 - [ 1 -(4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3 -dihydro-indol- 1 - ylmethyl}-phenoxy)-acetic acid ethyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-N-isopropyl-benzamide;
6-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl} -nicotinic acid methyl ester;
2- {3-[l -(4-Chloro-phenyl)- l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-thiazole-4-carboxylic acid ethyl ester;
3- [1 -(4-Chloro-phenyl)- 1 -phenyl-meth- (E) -ylidene] -1 -(4-methoxy-benzyl)- 1,3-dihydro- indol-2-one;
3 - [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] - 1 - (3 ,4,5 -trihydroxy-benzyl) - 1 ,3 - dihydro-indol-2-one;
3 - [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (Z) -ylidene] - 1 - (3 ,4,5 -trihydroxy-benzyl) - 1 ,3 - dihydro-indol-2-one;
3- [1 -(4-Chloro-phenyl)- 1 -phenyl-meth- (E) -ylidene] -1 -(4-hydroxy-benzyl)- 1,3-dihydro- indol-2-one;
3-{3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Fluoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Methoxy-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid;
3-{2-Oxo-3-[l -phenyl- l-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid;
3-{2-Oxo-3-[l -phenyl- l-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid; 3 -{3 - [ 1 -(3 -Chloro-4-fluoro-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 -dihydro- indol-l-ylmethyl}-benzoic acid;
3-{2-Oxo-3-[l-phenyl-l-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-
1- ylmethyl}-benzoic acid; 3-{3-[l-(3-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid;
3-{3-[l-(3,5-Dichloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(2,3-Dichloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
2- {3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid; 4-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3- {3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
6-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl} -nicotinic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid; 3-{3-[l-(2-Methylsulfanyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol- 1 -ylmethylj-benzoic acid;
3-{2-Oxo-3-[l-phenyl-l-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-l-ylmethylJ- benzoic acid; 3-{3-[l-(2-Chloro-5-trifluoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene] -2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
3-{3-[l-(3,5-Bis-trifluoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{2-Oxo-3-[l-phenyl-l-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{2-Oxo-3-[l-phenyl-l-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene] -2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
(4-{3 - [ 1 -(4-Chloro-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 -dihydro-indol- 1 - ylmethyl}-phenoxy)-acetic acid;
3 -{3 - [ 1 -(4-Isopropyl-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 -dihydro-indol- 1 - ylmethylj-benzoic acid;
3-{3-[l-(3,4-Difluoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{5-Chloro-3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{3-[l-(2-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
2- {3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-thiazole-4-carboxylic acid;
3- {3-[4-Methyl-l-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester; 3-{3-[3,3-Dimethyl-l-phenyl-but-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester;
3-{3-[2-(4-Chloro-phenyl)-l-phenyl-eth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[3,3-Dimethyl-l-phenyl-but-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester;
3-{3-[4-Methyl-l-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid;
3-{3-[l-(4-Chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Fluoro-phenyl)-eth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[2-Methyl-l-phenyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester;
3-{3-[l-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[2-Methyl-l-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Cyano-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester; 3-{3-[l-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
6-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid;
6-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid;
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid;
3-{3-[l-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid;
3-{3-[l-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
6-{3-[l-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid;
3-{3-[2-Methyl-l-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethylJ benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid;
3-{3-[2-Methyl-l-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid; 3-{3-[2-Methyl-l-thiophen-3-yl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{5-Chloro-3-[2-methyl-l-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene] -2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid; 3-{3-[l-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
N-(3-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoyl)-methanesulfonamide;
N-(3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol- l-ylmethyl}-benzoyl)-methanesulfonamide; and
N-(3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol- l-ylmethyl}-benzoyl)-methanesulfonamide; or a pharmaceutically acceptable salt or ester thereof.
Also particularly preferred is a compound of formula (I) selected from 3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
6-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid; and
6-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid; or a pharmaceutically acceptable salt or ester thereof.
The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds are provided in the examples. Generally, compounds of formula (I) can be prepared according to the schemes illustrated below. In the following schemes, Ar is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, thiazolyl or substituted thiazolyl, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, wherein substituted pyridinyl and substituted thiazolyl are pyridinyl and thiazolyl substituted with alkoxycarbonyl or carboxy. R8 is independently selected from alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy or alkylcarbonyl as mono- substituent, bi-substituent or tri-substituent. R1 to R7 are as defined above unless otherwise indicated.
Scheme 1
Figure imgf000017_0001
IV la
One method for synthesizing compounds of the invention is set forth in Scheme 1, wherein the oxindoles la are prepared. In this process, the condensation reaction between the substituted oxindoles II and the substituted acetophenones III gives the intermediates IV, which subsequently undergo coupling reaction in the presence of copper salts catalyst to produce compounds la.
In the first step outlined in Scheme 1, intermediates IV can be prepared by a condensation reaction between the substituted oxindoles II and the substituted
acetophenones III. The reaction can be carried out in the presence of an organic base such as piperidine or pyrolidine, in an organic solvent such as methanol, ethanol, toluene or the mixture thereof, under reflux overnight.
The intermediates IV couple with the aryl halides V to afford the compounds of formula la. The coupling reaction can be carried out in the presence of a copper catalyst such as copper(I) iodide (Cul), in combination with a ligand such as 2,2'-bipyridine, proline, Ν,Ν'-imethyl glycine or ethylene glycol, and a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert- butoxide, potassium tert-butoxide, sodium hydride, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable organic solvent such as acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4-dioxane, N,N- dimethylformamide, dimethyl sulfoxide, N-methylpyrolidinone or a mixture thereof, at a temperature between 100 and 180°C for 15 to 60 minutes under microwave irradiation. Alternatively, the reaction can be carried out at elevated temperature such as 80°C for a longer reaction time without microwave irradiation (Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).
Scheme 2
Figure imgf000018_0001
IV VI I lb
The compounds of formula lb can be prepared according to Scheme 2. In this process, the condensation reaction between the compounds IV and the commercially available reagents VI gives the intermediates VII, which subsequently undergo a hydrolysis reaction to afford the compounds of formula lb.
In the first step outlined in Scheme 2, starting materials IV can be obtained through the synthetic method illustrated in Scheme 1. The intermediates VII can be prepared by an alkylation reaction between VI and IV when using base such as sodium hydride, potassium carbonate or cesium carbonate in organic solvent such as tetrahydrofuran, Ν,Ν-dimethylformamide or the mixture thereof, at room temperature for several hours.
Finally, hydrolysis of the methyl ester VII affords the compounds lb. Hydrolysis of the methyl esters can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours.
Scheme 3
Figure imgf000019_0001
Figure imgf000019_0002
The compounds of formula Ic can be prepared according to Scheme 3. This approach is based on a highly efficient palladium- catalyzed synthesis of asymmetrically substituted 3-(diarylmethylenyl)indolinones from readily accessible starting materials. Many combinations of substituted aniline XII and substituted iodobenzene XIII are used in this reaction. This reaction can be carried out successfully in the presence of catalytic amount of Pd(OAc)2, using Ν,Ν-dimethylformamide as solvent and NaOAc as a base. The reaction usually takes place at 110°C and needs several hours to complete (Artur Pinto et al., Org. Lett. 4927, 2006). The amides X can be prepared by the coupling reaction between aniline VIII and carboxylic acid IX in the presence of coupling reagent such as 1,3- dicyclohexylcarbodiimide.
Intermediate XII can be prepared by alkylation reaction between XI and X. The reaction usually needs sodium hydride, potassium carbonate or cesium carbonate as a base and is carried out at room temperature for several hours in organic solvent such as tetrahydrofuran or N,N-dimethylformamide.
Scheme 4
Figure imgf000019_0003
Id XIV can be prepared by the method described in Scheme 3. Treatment of XIV with boron tribromide in dichloromethane successfully affords Id.
Scheme 5
Figure imgf000020_0001
XV can be prepared by the method described in Scheme 3. Hydrolysis of XV in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide successfully affords acid Ie.
Scheme 6
Figure imgf000020_0002
XVI XVII ig
The compounds of formula If and Ig can be prepared according to Scheme 6. This approach is based on Nickel catalyzed carboannulation reaction of zinc reagents XVII with unsaturated compounds XVI (Ruixue Deng, et al., Org. Lett. 5207, 2007).
The starting material XVI can be prepared according to the method described in Scheme 3.
Scheme 7
Figure imgf000021_0001
The compounds of formula Ih and Ii can be prepared according to Scheme 7.
Hydrolysis of If and Ig in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide successfully affords acids Ih and Ii.
Scheme 8
Figure imgf000021_0002
XVl ll XX The compounds of formula Ij can be prepared according to Scheme 8. The key step is the palladium catalyzed Heck-Carbocyclization/Suzuki-Coupling Reaction between iodide XVIII and boronic acid XIX in the presence of catalytic amount of Pd(PPh3)4. This reaction proceeds smoothly when using CsF or copper thiophene-2-carboxylic acid as base (Reiko, Y. et al., J.Org.Chem. 70, 6972, 2005; Wing S.Cheung, et al., J.Org.Chem. 70, 3741, 2005).
Hydrolysis of XX in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide successfully affords acids Ij.
The starting material XVIII can be prepared according to the procedure described in Scheme 3.
Scheme 9
Figure imgf000022_0001
The compounds of formula Ik can be prepared according to Scheme 9. The key step is the palladium catalyzed Heck-Carbocyclization/Suzuki-Coupling Reaction between iodide XXVI and boronic acid XXVII in the presence of catalytic amount of Pd(PPh3)4. This reaction proceeds smoothly when using CsF or copper thiophene-2-carboxylic acid as base (Reiko, Y. et al., J.Org.Chem. 70, 6972, 2005; Wing S.Cheung, et al., J.Org.Chem. 70, 3741, 2005).
The amide XXVI can be prepared by the alkylation between amide XXIV and benzyl bromide XXV as described in Scheme 3. Amide XXIV can be prepared by reacting isocyanate XXII with lithium reagent XXIII generated from n-butyl lithium and acetylene. The isocyanate XXII can be prepared by treating 2-iodo-anilines XXI with triphosgene in organic solvent such as dichloromethane in the presence of saturated aqueous sodium bicarbonate solution.
Scheme 10
Figure imgf000022_0002
The compounds of formula II can be prepared according to Scheme 10. Hydrolysis of ester Ik in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide successfully affords acid II.
Scheme 11
Figure imgf000023_0001
The compounds of formula Im can be prepared according to Scheme 11. Treatment of acid II with methylsulfonamide in the presence of coupling reagent such as l-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and organic base such as DMAP for hours successfully affords compound Im.
The invention also relates to a process for the preparation of a compound of formula (I) comprising one of the following steps:
(a) the reaction of a compound according to formula (A)
Figure imgf000023_0002
in the presence R7-X and a copper catalyst;
(b) the reaction of a compound according to formula (B)
Figure imgf000023_0003
in the presence of R8-I and a palladium catalyst;
(c) the reaction of a compound according to formula (C)
Figure imgf000024_0001
in the presence of boron tribromide;
(d) the reaction of a compound according to formula (D)
Figure imgf000024_0002
in the presence of R6-ZnBr and a nickel catalyst;
(e) the reaction of a compound according to formula (E)
Figure imgf000024_0003
in the presence of a base;
(f) the reaction of a compound according to formula (F)
Figure imgf000025_0001
in the presence of R8 B(OH)2 and a palladium catalyst;
(g) the reaction of a compound according to formula (G)
Figure imgf000025_0002
in the presence of MeS02NH2 and a coupling reagent; wherein R1 to R7 are as defined above, wherein Ar is phenyl, substituted phenyl, pyridinyl or thiazolyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, wherein R10 is phenyl substituted with one to three substituents independently selected from alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl, wherein R9 is alkyl, wherein R11 is alkyl and wherein X is chloro or bromo.
R9 is preferably methyl or ethyl. R11 is preferably G-C4 alkyl, preferably methyl or ethyl, more preferably methyl.
The reaction of step (a) can be carried out in the presence of coupling reagent, such as a copper catalyst, such as copper(I) iodide (Cul), in combination with a ligand such as 2,2'-bipyridine, proline, Ν,Ν'-imethyl glycine or ethylene glycol, and a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable organic solvent such as acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4-dioxane, N,N- dimethylformamide, dimethyl sulfoxide, N-methylpyrolidinone or a mixture thereof. The reaction temperature can be for example between 100 and 180°C, e.g. for 15 to 60 minutes under microwave irradiation. Alternatively, the reaction can be carried out at a elevated temperature such as 80°C for a longer reaction time without microwave irradiation.
The reaction of step (b) can be carried out in the presence of catalytic amount of Pd(OAc)2, using Ν,Ν-dimethylformamide as solvent and NaOAc as a base. The reaction usually takes place at 110°C and may need several hours to complete.
Step (c) is preferably carried out in dichloromethane.
Step (e) can be carried out in a solvent such as methanol, 1,4-dioxane or
tetrahydrofuran, e.g. at room temperature for several hours. The base is preferably an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
The reaction of step (f) can be carried out in the presence of catalytic amount of Pd(PPh3)4. A base is preferably employed. This reaction proceeds smoothly when using CsF or copper thiophene-2-carboxylic acid as base.
The reaction of step (g) can be achieved in the presence of coupling reagent such as l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic base such as DMAP.
The invention also relates to a compound of formula (I) for use as therapeutically active substance.
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.
The use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to AMPK regulation is an object of the invention.
The invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia, type lor type 2 diabetes, in particular type 2 diabetes.
Said medicaments, e.g. in the form of pharmaceutical preparations, can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions with an effective amount of a compound as defined above.
The above-mentioned pharmaceutical composition can be obtained by processing the compounds according to this invention with pharmaceutically inert inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, can be used as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical composition can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, fiavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage depends on various factors such as manner of administration, species, age and/or individual state of health. The doses to be administered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg, and can be taken singly or distributed over several administrations.
A compound of formula (I) when manufactured according to the above process is also an object of the invention.
Furthermore, the invention also relates to a method for the treatment or prophylaxis of diseases that are related to AMPK regulation, which method comprises administering an effective amount of a compound of formula (I).
The invention further relates to a method for the treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes, in particular type 2 diabetes, which method comprises administering an effective amount of a compound of formula (I). Furthermore, the invention also relates to a compound of formula (I) for the preparation of medicaments useful in the treatment of cancers that are related to AMPK regulation and provides a method for the treatment of cancers that are related to AMPK regulation. The invention is illustrated by the following examples which have no limiting character. Unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.
Examples
Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module, ii) ISCO combi-fiash chromatography instrument. Silica gel Brand and pore size: i) KP-SIL 60 A, particle size: 40-60 uM; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.
Intermediates and final compounds were purified by preparative HPLC on reversed phase column using X BridgeTM Perp G8 (5 um, OBDTM 30 x 100 mm) column or SunFire™ Perp G8 (5 um, OBDTM 30 x 100 mm) column.
LC/MS spectra were obtained using a MicroMass Plateform LC (WatersTM alliance 2795-ZQ2000). Standard LC/MS conditions were as follows (running time 6 min):
Acidic condition: A: 0.1% formic acid in H20; B: 0.1% formic acid in acetonitrile;
Basic condition: A: 0.01% NH3.H20 in H20; B: acetonitrile; Neutral condition: A: H20; B: acetonitrile.
Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H)+.
The microwave assisted reactions were carried out in a Biotage Initiator Sixty.
NMR spectra were obtained using Bruker Avance 400MHz. All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.
In case a mixture of E and Z isomers is produced during a reaction, these isomers are separated by methods described herein or known to the man skilled in the art such as e.g. chromatography or crystallization.
Example 1
3-[2-Oxo-3-(l-phenyl-ethylidene)-2,3-dihydro-indol-l-yl]-benzoic acid ethyl ester
Figure imgf000030_0001
3- ( 1 -Phenyl-ethylidene) - 1 ,3-dihydro-indol-2-one
Oxindole (0.1332 g, 1 mmol), acetophenone (1.4 ml, 1.2 mmol) were mixed in toluene; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture was refluxing for 3h; the reaction was monitored by TLC. When the reaction was finished the solvent was removed under reduced pressure. The residue was separated by flash chromatography column (gradient elution, 10-25% ethyl acetate in petroleum ether) to give 3-(l-phenyl- ethylidene)-l,3-dihydro-indol-2-one as yellow powder (200 mg, 85%). ¾ NMR (400 MHz, DMSO-c¾ δ ppm 2.70 (s, 3 H) 5.96 (d, /=7.83 Hz, 1 H) 6.51 - 6.57 (m, 1 H) 6.77 (d, /=7.58 Hz, 1 H) 7.00 - 7.10 (m, 1 H) 7.30 - 7.37 (m, 2 H) 7.44 - 7.58 (m, 3 H) 10.54 (br. s., 1 H). MS calcd. for Ci6Hi3NO 235, obsd. (ESP) [(M+H)+] 236.
3-[2-Oxo-3-(l-phenyl-ethylidene)-2,3-dihydro-indol-l-yl]-benzoic acid ethyl ester
A Schlenk tube was charged with Cul (9.6 mg, 0.050 mmol, 5.0 mol %), 3-(l-phenyl- ethylidene)-l,3-dihydro-indol-2-one (352.7 mg, 1.5 mmol), and K2C03 (276 mg,
2.0mmol), evacuated, and backfilled with argon. N, W-dimethylethylenediamine (11 uL, 0.10 mmol, 10 mol %), ethyl 3-iodobenzoate (278.8 mg, 1.01 mmol), and acetonitrile (1.5 ml) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80°C for 23 h. The reaction was monitored by HPLC. When the reaction was finished, the solvent was removed under reduced pressure. The residue was separated by flash chromatography column (gradient elution, 5-10% ethyl acetate in petroleum ether) to give 3- [2-oxo-3-(l-phenyl-ethylidene)-2,3-dihydro-indol-l- yl] -benzoic acid ethyl ester as yellow powder (344 mg, 90%). ¾ NMR (400 MHz, CDC13) 5ppm 1.42 (t, J=7.20 Hz, 3 H) 2.87 (s, 3 H) 4.42 (q, J=7.07 Hz, 2H) 6.25 (d, J=7.58 Hz, 1 H) 6.68 - 6.78 (m, 2 H) 7.09 (t, J=7.71 Hz, 1 H) 7.34 - 7.40 (m, 2 H) 7.47 - 7.58 (m, 3H) 7.62 - 7.72 (m, 2 H) 8.11 - 8.19 (m, 2 H). MS calcd. for C25H21NO3 383, obsd. (ESP) [(M+H)+] 383.9.
Example 2
(3-{2-Oxo-3-[l-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-l-yl}-phenyl)-acetic acid methyl ester
Figure imgf000031_0001
The title compound was prepared in analogy to Example 1 starting from (3-bromo- phenyl) -acetic acid methyl ester (commercially available) and 3-[l-phenyl-eth-(E)- ylidene]-l,3-dihydro-indol-2-one. ¾ NMR (400 MHz, DMSO-d6) 5ppm 2.77 (s, 3 H) 3.65 (s,3H) 3.81(s, 2 H) 6.08 (d, J=7.33 Hz, 1 H) 6.66 -6.72 (m, 2 H) 7.11 (t, J=7.33 Hz, 1 H) 7.35 - 7.44 (m, 5 H) 7.51 - 7.61 (m, 4 H).
Example 3
2-Methyl-5-{2-oxo-3-[l-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-l-yl}-benzoic acid methyl ester
Figure imgf000031_0002
The title compound was prepared in analogy to Example 1 starting from 5-bromo-2- methyl-benzoic acid methyl ester (commercially available) and 3-[l-phenyl-eth-(E)- ylidene]-l,3-dihydro-indol-2-one. ¾ NMR (400 MHz, chloroform-d) 5ppm 2.71 (s, 3 H) 2.86 (s, 3 H) 3.91 (s, 3 H) 6.24 (d, J=7.83 Hz, 1H) 6.67 - 6.75 (m, 2 H) 7.08 (t, J=7.83 Hz, 1 H) 7.34 - 7.37 (m, 2 H) 7.43 - 7.47 (m, 1 H) 7.49 - 7.56 (m, 4 H)8.05 (d, J=2.27 Hz, 1 H).
Example 4
[2-Oxo-3- ( 1 -phenyl-ethylidene) -2, 3-dihydro-indol- 1 -yl] -acetic acid
Figure imgf000031_0003
3- ( 1 -Phenyl-ethylidene) - 1 ,3-dihydro-indol-2-one The synthetic method of 3-(l-phenyl-ethylidene)-l,3-dihydro-indol-2-one is described in Example 1.
[2-Oxo-3-(l-phenyl-ethylidene)-2,3-dihydro-indol-l-yl]-acetic acid methyl ester
3-(l-Phenyl-ethylidene)-l,3-dihydro-indol-2-one (294 mg, 1 mmol) was dissolved in anhydrous DMF, then methyl bromoacetate (184 mg, 1.2 mmol) was added. Finally, Cs2C03 (488 mg, 1.5 mmol) was added in one portion. The mixture was stirred at room temperature overnight. The reaction was monitored by HPLC. When the reaction was fmished, the solvent was removed under reduced pressure. The residue was separated by flash chromatography column (gradient elution, 5-10% ethyl acetate in petroleum ether) to give [2-oxo-3-(l-phenyl-ethylidene)-2,3-dihydro-indol-l-yl]-acetic acid methyl ester as yellow powder (230 mg, 75%). MS calcd. for G9H17NO3 307, obsd. (ESP) [(M+l)+] 308.1.
[2-Oxo-3- ( 1 -phenyl-ethylidene) -2, 3-dihydro-indol- 1 -yl] -acetic acid
[2-Oxo-3-(l-phenyl-ethylidene)-2,3-dihydro-indol-l-yl]-acetic acid methyl ester (50 mg, 0.16 mmol) was dissolved in menthol 1 ml; then 0.1 ml water was added. Finally, lithium hydroxide (10 mg) was added. The mixture was stirred overnight. The reaction was monitored by HPLC. When the reaction was finished, the solvent was removed under reduced pressure. The residue was dissolved in 2 ml DMF for prepared HPLC to give [2- oxo-3-(l-phenyl-ethylidene)-2, 3 -dihydro-indol-l-yl] -acetic acid as white powder (11 mg). ¾ NMR (400 MHz, CDC13) δ ppm 2.82 (s, 3 H) 4.61 (s, 2 H) 6.20 (d, J=7.58 Hz, 1 H) 6.66 -6.73 (m, 2 H) 7.14 (t, J=7.58 Hz, 1 H) 7.31 (s, 2 H) 7.46 - 7.54 (m, 3 H). MS calcd. for C18H15NO3 293, obsd. (ESF) [(M+H)+] 294.1.
Example 5
3- ( (3- ( (4-Chlorophenyl) (phenyl) meth- (E) -ylene) -2-oxoindolin- 1 -yl)methyl)benzoic acid methyl ester
Figure imgf000032_0001
3-Phenyl-propynoic acid phenylamide
Phenylamine (1.86 g, 20 mmol) and phenylpropiolic acid (3.22 g, 22 mmol) were dissolved in dichloromethane (50 ml) and 1,3-dicyclohexylcarbodiimide (4.8 g, 23.2 mmol) was added in one portion at 0°C. The mixture was stirred room temperature for 14 h. The mixture was poured into water and extracted with dichloromethane (3 x 15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica gel, eluting with hexanes- EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenylamide 2.7 g (62%).
3-{[Phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester
3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol), 3-bromomethyl-benzoic acid methyl ester (1.2 g, 5.16 mmol) and Cs2C03 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3 -{[phenyl-(3 -phenyl - propynoyl)-amino]-methyl}-benzoic acid methyl ester 1.03 g (65%). 3-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
To a solution of 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester (369.4 mg, 1 mmol) in THF (5 ml) were added palladium(II) acetate (11.2 mg, 0.05 mmol), triphenylphosphine (26.2 mg, 0.1 mmol), l-chloro-4-iodobenzene (262.3mg, 1.1 mmol) and cesium fluoride (456 mg, 3 mmol) at room temperature. The solution was stirred for 3 h at 110 °C under an argon atmosphere. After being quenched with water, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with (hexane/ethyl acetate = 5/1) to give 3-{3-[l-(4-chloro-phenyl)-l- phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester .yield 297mg (62%); ¾ NMR (CDC13, 300 MHz) δ ppm 8.00(s,lH), 7.92(d,lH),
7.50(d,lH), 7.26-7.43(m,10H), 7.08(dt,lH), 6.71(dt,lH), 6.59(d,lH), 6.52(d,lH),
4.95(s,2H), 3.90(s,3H).
Example 6 3-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -7-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000034_0001
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 3-{[(2-fiuoro-phenyi)-(3-phenyl-propynoyi)- amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.88(s,3H), 5.11(s,2H), 6.22(d,lH), 6.61-6.67(m,lH), 6.82-6.89 (dd,lH), 7.26-7.43 (m,10H),
7.52(d,lH), 7.92(d,lH), 8.01(s,lH).
Example 7
3-(3-Benzhydrylidene-2-oxo-2,3-dihydro-indol-l-ylmethyl)-benzoic acid methyl ester
Figure imgf000034_0002
The title compound was prepared in analogy to Example 5 starting from iodo-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.01(s,lH), 8.00(d,lH), 7.93(d,lH), 7.33-7.52(m,12H), 7.05(dt,lH), 6.66(m,2H), 6.43(d,2H), 4.96(s,2H), 3.91(s,3H).
Example 8 3-{3- [ 1 - (4-Methoxy-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000034_0003
The title compound was prepared in analogy to Example 5 starting from 1-iodo 4- methoxy-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl) -amino] - methylj-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.01(s,lH), 7.94(d,lH), 7.49(d,lH), 7.26-7.38(m,8H), 7.06(m,lH), 6.94(m,2H), 6.63-6.70(m,3H), 4.97(s,2H), 3.91(s,3H), 3.88(s,3H).
Example 9
3-{2-Oxo-3-[l-phenyl-l-p-tolyl-meth-(E)-ylidene]-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester
Figure imgf000035_0001
The title compound was prepared in analogy to Example 5 starting from l-methyl-4-iodo- benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)-amino]-methyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.01(s,lH), 7.92(d,lH), 7.24- 7.52(m,l lH), 7.05(t,lH), 7.56-7.71(m,3H), 4.96(s,2H), 3.91(s,3H), 2.44(s,3H).
Example 10
3-{3-[l-(4-Chloro-phenyl)-l-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000035_0002
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 3-({[3-(2-methoxy-phenyl)-propynoyl]-phenyl- amino}-methyl)-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 7.99(s,lH), 7.92(d,lH), 7.26-7.49(m,7H), 6.93-7.15(m,4H), 6.72(t,lH), 6.61-6.64(m,2H), 4.93(dd,2H), 3.90(s,3H), 3.63(s,3H). Example 11
3-{3- [ 1 - (4-Cyano-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000036_0001
The title compound was prepared in analogy to Example 5 starting from 4-iodo- benzonitrile (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl) -amino] - methylj-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.00(s,lH),
7.93(d,lH), 7.74-7.76(m,2H), 7.35-7.51(m,9H), 7.10(t,lH), 6.56-6.72(m,2H), 6.35(d,lH), 4.95(s,2H), 3.91(s,3H)
Example 12
3-{2-Oxo-3-[l-phenyl-l-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000036_0002
The title compound was prepared in analogy to Example 5 starting from l-iodo-4- trifiuoromethyl-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)- amino] -methylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13) 5ppm 3.91(s ,3H), 4.96(s,2H), 6.37(d,lH), 6.67(dd,2H), 7.08(t,lH), 7.35-7.40(m,7H) ,7.49(d,2H) ,7.71(d,2H), 7.95(d,lH), 8.01(s,lH).
Example 13
3-{3-[l-(3-Chloro-4-fluoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000036_0003
The title compound was prepared in analogy to Example 5 starting from 2-chloro-l- fiuoro-4-iodo-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)- amino]-methyl}-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.00(s,lH), 7.93(d,lH), 7.50(d,lH), 7.22-7.42(m,9H), 7.09(dt,lH), 6.73(dt,lH), 6.66(d,lH), 6.51(d,lH), 4.95(s,2H), 3.91(s,3H).
Example 14
3-{2-Oxo-3-[l-phenyl-l-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000037_0001
The title compound was prepared in analogy to Example 5 starting from 5-Iodo-l,2,3- trimethoxy-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)- amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm
3.76(s,6H),3.91(s,3H),3.94(s,3H), 4.96(s,2H), 6.55(s,2H),6.61-6.71(m,4H),7.06(t,lH),7.38- 7.40 (m,5H), 7.53(d,lH), 7.91(d,lH), 8.02(s,lH). Example 15
3-{3- [ 1 - (3,4-Difluoro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000037_0002
The title compound was prepared in analogy to Example 5 starting from l,2-difiuoro-4- iodo-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl) -amino] - methylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.90(s,3H), 4.96(s,2H), 6.58(d,lH), 6.70(m,2H), 7.07-7.32(m,4H), 7.34-7.43 (m,6H), 7.50(d,lH), 7.94(d,lH), 8.02(s,lH).
Example 16 3-{3- [ 1 - (3-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000038_0001
The title compound was prepared in analogy to Example 5 starting from l-chloro-3-iodo- benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)-amino]-methyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.01(s,lH), 7.93(d,lH), 7.50(d,lH), 7.26-7.46(m,10H), 7.08(t,lH), 6.70(t,lH), 6.65(d,lH), 6.44(d,lH), 4.96(s,2H), 3.90(s,3H).
Example 17 3-{3- [ 1 - (2-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000038_0002
The title compound was prepared in analogy to Example 5 starting from l-chloro-2-iodo- benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)-amino]-methyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.01(s,lH), 7.92(d,lH), 7.50- 7.52(m,4H), 7.37-7.42(m,7H), 7.07(t,lH), 6.62-6.69(m,lH), 6.05(d,lH), 4.96(dd,2H), 3.91(s,3H).
Example 18
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000039_0001
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 3-{[(4-fiuoro-phenyi)-(3-phenyl-propynoyi)- amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDCI3): 5ppm
3.91(s,3H),4.94(s,2H),6.25(dd,lH),6.54(dd,2H), 6.75-6.80(m,lH), 7.10(d,2H), 7.33- 7.54(m,8H), 7.94(d,lH),7.98(s,lH).
Example 19
3-{3- [ 1 - (3,5-Dichloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000039_0002
The title compound was prepared in analogy to Example 5 starting from l,3-dichloro-5- iodobenzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl) -amino] - methylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.92(s,3H), 4.95(s,2H), 6.47(d,lH), 6.65-6.78(m,2H), 7.13 (t,2H), 7.33-7.43 (m,8H), 7.52(d,lH), 7.93(d,lH), 8.01(s,lH).
Example 20
3-{3- [ 1 - (2,3-Dichloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000039_0003
The title compound was prepared in analogy to Example 5 starting from l,2-dichloro-3- iodobenzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl) -amino] - methylj-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.00(s,lH),
7.92(d,lH), 7.33-7.54(m,9H), 7.23(dd,lH), 7.10(t,lH), 6.74(t,lH), 6.66(d,lH),6.55(d,lH), 4.95(s,2H), 3.90(s,3H).
Example 21
4-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000040_0001
The title compound was prepared in analogy to Example 5 starting from l-chloro-4- iodobenzene (commercially available) and 4- {[phenyl- (3 -phenyl propynoyl) -amino] - methylj-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 7.97(d,lH), 7.25- 7.43(m,12H), 7.07(dt,lH), 6.71(dt,lH), 6.61(d,lH), 6.54(d,lH), 4.97(s,2H), 3.89(s,3H).
Example 22 3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000040_0002
The title compound was prepared in analogy to Example 5 starting from l-chloro-4- iodobenzene (commercially available) and 3-{[(4-methoxy-phenyl)-(3-phenyl- propynoyl) -amino] -methylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.49(s,3H), 3.91(s,3H), 4.92(s,2H),6.10(dd,lH), 6.51(d,lH), 6.62 (dd,lH), 7.25-7.50 (m,l lH), 7.93(d,lH), 7.99(s,lH).
Example 23 3-{3-[l-(2-Bromo-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid methyl ester
Figure imgf000041_0001
The title compound was prepared in analogy to Example 5 starting from l-bromo-2- iodobenzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl) -amino] - methylj-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.01(s,lH),
7.93(d,lH), 7.71(d,lH), 7.30-7.53(m,l lH), 7.04-7.09(m,2H), 6.62-7.04(m,3H), 6.42(d,lH), 6.02(d,lH), 4.88-5.05(m,2H), 3.91(s,3H).
Example 24 3-{3-[l-(2-Chloro-5-trifluoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene] -2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000041_0002
The title compound was prepared in analogy to Example 5 starting from l-chloro-2-iodo- 4-trifiuoromethyl-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl) -amino] -methylj-benzoic acid methyl ester. ¾ NMR (CDCi3,300MHz) 5ppm 8.01(s,lH), 7.93(d,lH), 7.63-7.67(m,2H), 7.33-7.52(m,7H), 7.10(t,lH), 6.64-6.71(m,2H), 5.98(d,lH), 4.87-5.04(m,2H), 3.91(s,3H).
Example 25
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000042_0001
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 3-{[(3-fiuoro-phenyi)-(3-phenyl-propynoyi)- amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.97(s,2H), 6.39-6.51(m,2H), 7.25-7.45 (m,l lH), 7.53(d,lH), 7.99(d,lH), 8.00(s,lH).
Example 26
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000042_0002
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 3-{[(3-fiuoro-phenyl)-(3-phenyl-propynoyl)- amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.90(s,3H), 4.96(s,2H), 6.48(d,lH), 7.10 (d,lH), 7.19(d,lH), 7.31-7.50 (m,l lH), 7.94(d,lH),
7.98(s,lH). Example 27
3-{3-[l-(3-Bromo-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid methyl ester
Figure imgf000042_0003
The title compound was prepared in analogy to Example 5 starting from l-bromo-3- iodobenzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl) -amino] - methylj-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.01(s,lH),
7.93(d,lH), 7.31-7.61(m,l lH), 7.08(t,lH), 6.64-6.73(m,2H), 6.44(d,lH), 4.95(s,2H), 3.91(s,3H).
Example 28
3-{3-[l-(2-Methylsulfanyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000043_0001
The title compound was prepared in analogy to Example 5 starting from l-iodo-2- methylsulfanyl-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)- amino] -methylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 2.31(s,3H), 3.90(s,3H), 5.00(dd,2H), 6.03(d,lH), 6.60 -6.64(m,2H),7.04(t,lH) , 7.26-7.30 (m,2H), 7.33-7.56(m,9H),7.95(d,lH), 8.01(s,lH). Example 29
3-{7-Chloro-3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000043_0002
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 3-{[(2-chloro-4-fiuoro-phenyl)-(3-phenyl- propynoyl) -amino] -methylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.90(s,3H), 5.38(s,2H), 6.01(dd,lH), 6.80 (dd,lH), 7.27-7.40 (m,9H), 7.45- 7.50(m,3H),7.92(m,2H).
Example 30 3-{2-Oxo-3-[l-phenyl-l-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000044_0001
The title compound was prepared in analogy to Example 5 starting from l-iodo-3- trifiuoromethyl-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)- amino]-methyl}-benzoic acid methyl ester. Ή NMR (CDCl3,300MHz) 5ppm 8.01(s,lH), 7.95(d,lH), 7.72(d,lH), 7.50-7.63(m,3H), 7.36-7.42(m,4H), 7.08(t,lH), 6.64-6.68(m,2H), 6.42(d,lH), 4.96(s,2H), 3.91(s,3H).
Example 31
3-{2-Oxo-3-[l-phenyl-l-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-l- ylmethyl}-benzoic acid methyl ester
Figure imgf000044_0002
The title compound was prepared in analogy to Example 5 starting from 4-iodo- benzenesulfonamide (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)- amino] -methylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.90(s,3H), 4.95(s,2H),5.02(s,2H), 6.41(d,lH), 6.65 -6.71 (m,2H), 7.09(t,lH), 7.26-7.33 (m,2H), 7.35- 7.42(m,6H),7.58-7.60(m,3H), 7.99(d,lH), 8.07(s,lH).
Example 32
3-{3-[l-(2-Methanesulfonyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000045_0001
The title compound was prepared in analogy to Example 5 starting from l-iodo-2- methanesulfonyl-benzene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)- amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDCI3): 5ppm
1.89(s,1.5H),2.50(s,1.5H), 3.90(s,3H),4.98(dd,2H), 5.98(dd,lH), 6.65 -6.68 (m,2H), 7.07(m,lH), 7.35-7.58(m,8H),7.61 (t,lH), 7.78(t,lH),7.99(d,lH), 8.02(d,lH),8.20(d,lH).
Example 33
3-{2-Oxo-3- [ 1 -phenyl- 1 -thiophen-3-yl-meth-(E)-ylidene] -2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000045_0002
The title compound was prepared in analogy to Example 5 starting from 3-iodo-thiophene (commercially available) and 3 -{[phenyl-(3 -phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.91(s,3H), 4.96(s,2H), 6.65(d,lH), 6.76-6.82 (m,2H), 7.06-7.1 l(m,2H), 7.33-7.43(m,8H),7.50 (d,lH), 7.92 (d,lH), 8.01(s,lH). Example 34
3-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (Z) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000045_0003
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.91(s,3H),4.96(s,2H), 6.42(d,lH), 6.63-6.66 (m,2H), 7.06(t,lH),7.33-7.52(m,l lH),7.92 (d,lH), 8.01(s,lH).
Example 35
3-{3- [ 1 - (4-Chloro-phenyl) - 1 - (4-trifluoromethyl-phenyl) -meth- (Z) -ylidene] -2-oxo-2,3- dihydro-indol- 1 -ylmethyl}-benzoic acid methyl ester
Figure imgf000046_0001
The title compound was prepared in analogy to Example 5 starting from l-iodo-4- trifiuoromethyl-benzene (commercially available) and 3-({[3-(4-chloro-phenyl)- propynoyl]-phenyl-amino}-methyl)-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.91(s,3H), 4.96(s,2H), 6.37(d,lH), 6.66-6.71 (m,2H), 7.08(t,lH), 7.26- 7.52(m,9H),7.73(d,2H), 7.94(d,lH), 8.01(s,lH).
Example 36
(4-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-phenoxy)-acetic acid ethyl ester
Figure imgf000046_0002
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and (4-{[phenyl-(3-phenyl-propynoyl)-amino]- methyl}-phenoxy)-acetic acid ethyl ester. ¾ NMR (300Hz, CDC13): 5ppm
1.28(t,3H),4.26(q,2H), 4.57(s,2H), 4.84(s,2H), 6.51(d,lH), 6.67-6.71(m, 2H), 6.83(d,2H), 7.08(t,lH), 7.24-7.42(m,l 1H).
Example 37 3-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-N-isopropyl-benzamide
Figure imgf000047_0001
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and N-isopropyl-3-{[phenyl-(3-phenyl-propynoyl)- amino]-methyl}-benzamide. ¾ NMR (CDCl3,300MHz) 5ppm 7.74(s,lH), 7.60(d,lH), 7.26-7.43(m,10H), 7.07(dt,2H),6.70(t,lH), 6.68(d,lH), 6.53(d,lH), 5.99(d,lH),
4.94(s,2H),4.26(m,lH), 1.26(s,3H), 1.24(s,3H).
Example 38
6-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylm ethyl} -nicotinic acid methyl ester
Figure imgf000047_0002
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 6-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}- nicotinic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.93(s,3H), 5.10(s,2H), 6.54(d,lH), 6.57-6.75(m, 2H), 7.08(t,lH), 7.28-7.44(m,10H), 8.20(d,lH), 9.16(s,lH).
Example 39
2-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-thiazole-4-carboxylic acid ethyl ester
Figure imgf000048_0001
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 2-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}- thiazole-4-carboxylic acid ethyl ester. ¾ NMR (300Hz, CDC13): 5ppm 1.39(t,3H), 4.44(q,2H), 5.27(s,2H), 6.58(d,lH), 6.78(t,lH), 6.88(d,lH), 7.13(t,lH), 7.31-7.43 (m,9H), 8.10(s,lH).
Example 40
3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] - 1 - (4-methoxy-benzyl) -1,3- dihydro-indol-2-one
Figure imgf000048_0002
The title compound was prepared in analogy to Example 5 starting from l-chloro-4-iodo- benzene (commercially available) and 3-phenyl-propynoic acid (4-methoxy-benzyl) - phenyl-amide. ¾ NMR (300Hz, CDC13): 5ppm 3.77(s,3H), 4.88(s,2H), 6.53(d,lH), 6.67- 6.71(m,2H), 6.80(dd,lH), 6.85-6.90(m,2H), 7.07 (t,lH), 7.19-7.43(m,10H). Example 41
3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] - 1 - (3,4,5-trihydroxy-benzyl) -1,3- dihydro-indol-2-one; and
Example 42
3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (Z) -ylidene] - 1 - (3,4,5-trihydroxy-benzyl) -1,3- dihydro-indol-2-one
Figure imgf000049_0001
3-Phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-amide
3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol), 5-bromomethyl-l,2,3- trimethoxy-benzene (1.35 g, 5.16 mmol), and Cs2C03 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-amidel.03 g (65%). 3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] - 1 - (3,4,5-trimethoxy-benzyl) -1,3- dihydro-indol-2-one and 3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (Z) -ylidene] - 1 - (3,4,5-trimethoxy-benzyl)-l,3-dihydro-indol-2-one
To a solution of 3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-amide (401.5 mg, 1 mmol) in THF (5 ml) were added palladium(II) acetate (11.2 mg, 0.05 mmol), triphenylphosphine (26.2 mg, 0.1 mmol), l-chloro-4-iodobenzene (262.3mg, 1.1 mmol) and cesium fluoride (456 mg, 3 mmol) at room temperature. The solution was stirred for 3 h at 110°C under an argon atmosphere. After being quenched with water, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with (hexane/ethyl acetate = 5/1) to give a mixture of 3-[l-(4-chloro-phenyl)-l- phenyl-meth-(E)-ylidene]-l-(3,4,5-trimethoxy-benzyl)-l,3-dihydro-indol-2-one and 3-[l- (4-chloro-phenyl)-l-phenyl-meth-(Z)-ylidene]-l -(3,4,5-trimethoxy-benzyl)- 1,3-dihydro- indol-2-one ,yield 317mg (62%);
3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] - 1 - (3,4,5-trihydroxy-benzyl) -1,3- dihydro-indol-2-one and 3-[l-(4-chloro-phenyl)-l-phenyl-meth-(Z)-ylidene]-l-(3,4,5- trihydroxy-benzyl)-l,3-dihydro-indol-2-one
To a solution of 3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-l-(3,4,5-trimethoxy- benzyl)-l,3-dihydro-indol-2-one and 3-[l-(4-chloro-phenyl)-l-phenyl-meth-(Z)- ylidene]-l-(3,4,5-trimethoxy-benzyl)-l,3-dihydro-indol-2-one (317mg, 0.62 mmol) in dichloromethane (5 ml) was added a solution of boron tribromide (1M in CH2C12, 3 ml) at room temperature. The mixture was stirred at room temperature for 5 h. After being quenched by pouring into ice water, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with (hexane/ ethyl acetate = 1/1) to give 3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-l-(3,4,5-trihydroxy- benzyl)-l,3-dihydro-indol-2-one (60 mg). ¾ NMR (300Hz, CDC13): 5ppm 4.66(s,2H), 5.60(b,lH),6.31(s,2H), 6.56(d,lH), 6.67-6.82(m,2H), 7.00-7.23(m,8H), 7.38 (d,2H); and 3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (Z) -ylidene] - 1 - (3 ,4,5 -trihydroxy-benzyl) - 1 ,3 - dihydro-indol-2-one (40 mg). ¾ NMR (300Hz, CDC13): 5ppm 4.72(s,2H), 5.33(b,lH), 6.05(b,lH), 6.40(s,2H), 6.44(d,lH), 6.67(t,lH), 6.82(d,lH), 7.00(d,2H), 7.10-7.15(m, 3H), 7.23-7.26 (m,2H), 7.37-7.46 (m,3H).
Example 43
3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] - 1 - (4-hydroxy-benzyl) -1,3- dihydro-indol-2-one
Figure imgf000050_0001
The title compound was prepared in analogy to Example 41 starting from 3-[l-(4-chloro- phenyl)-l-phenyl-meth-(E)-ylidene]-l-(4-methoxy-benzyl)-l,3-dihydro-indol-2-one. ¾ NMR (300Hz, CDC13): 5ppm 4.81(s,2H), 6.51(d,lH), 6.53-6.74(m, 4H), 7.08-7.1 l(m,3H), 7.24-7.42(m,9H).
Example 44
3-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000050_0002
3-{3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester (94 mg, 0.2 mmol) was dissolved in THF (2 ml) and water (2 ml) and LiOH.H20 (42 mg, 1 mmol) was added in one portion. The mixture was stirred at 50°C for 16 h. The mixture was concentrated under reduced pressure, and acidified to pH=3. Purification by preparative HPLC afforded 3-((3-((4- chlorophenyl)(phenyl)meth-(E)-ylene)-2-oxoindolin-l-yl)methyl)benzoic acid as light yellow powder. Yield 30 mg (70%). ¾ NMR (CDC13, 300 MHz) δ ppm 8.06(s,lH), 7.99(d,lH), 7.55(d,lH), 7.29-7.43(m,10H), 7.09(t,lH), 6.74-6.65(m,2H), 6.55(d,lH),
Example 45 3-{3- [ 1 - (4-Fluoro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000051_0001
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- fiuoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.07(s,lH), 8.00(d,lH),
7.56(d,lH), 7.33-7.48(m,8H), 7.07-7.17(m,3H), 6.66-6.74(m,2H), 6.52(d,lH), 4.99(s,2H).
Example 46
3-{3- [ 1 - (4-Methoxy-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
—
Figure imgf000051_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- methoxy-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.07(s,lH), 8.00(d,lH), 7.55(d,lH), 7.26-7.38(m,8H), 7.07(m,lH), 6.94(m,2H), 6.65-6.71(m,3H), 4.98(s,2H), 3.88(s,3H).
Example 47
3-{3- [ 1 - (4-Chloro-phenyl) - 1 - (2-methoxy-phenyl) -meth- (Z) -ylidene] -2-oxo-2,3- dihydro-indol- 1 -ylmethyl}-benzoic acid
Figure imgf000052_0001
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- chloro-phenyl)-l-(2-methoxy-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid methyl ester. ¾ NMR (CDC13, 300MHz) 5ppm 8.04(s,lH), 7.99(d,lH), 7,54(d,lH), 7.32-7.44(m,6H), 7.07-7.15(m,2H), 6.93-7.01(m,2H), 6.73(t,lH), 6.64(t,2H), 4.95(dd,2H), 3.90(s,3H), 3.72(s,3H).
Example 48
3-{2-Oxo-3-[l-phenyl-l-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000052_0002
The title compound was prepared in analogy to Example 44 starting from 3-{2-oxo-3-[l- phenyl-l-(4-trifiuoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-l -ylmethylj- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm
4.98(s,2H),6.40(d,lH),6.68(dd,2H),7.10(t,lH), 7.35-7.55(m,9H), 7.71(d,2H), 7.99(d,lH), 8.07(s,lH).
Example 49 3-{2-Oxo-3-[l-phenyl-l-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000053_0001
The title compound was prepared in analogy to Example 44 starting from 3-{2-oxo-3-[l- phenyl- l-(2-trifiuoromethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.91 (s,3H,), 5.96(s,2H), 6.37(d,lH), 6.64-6.72(m,2H),7.07(dt,lH), 7.51-7.33(m,H),7.70(d,2H) 7.93(d,lH),
8.01(s,lH).
Example 50 3-{3- [ 1 - (3-Chloro-4-fluoro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000053_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(3- chloro-4-fiuoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester. ¾ NMR (CDC13, 300MHz) 5ppm 8.07(s,lH), 8.01(d,lH), 7.56(d,lH), 7.34-7.45(m,6H), 7.22-7.28(m,3H), 7.11(dt,lH), 6.74(dt,lH), 6.68(d,lH), 6.53(d,lH), 4.98(s, 2H).
Example 51
3-{2-Oxo-3-[l-phenyl-l-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000054_0001
The title compound was prepared in analogy to Example 44 starting from 3-{2-oxo-3-[l- phenyl-l-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.79(s,6H),3.94(s,3H), 4.98(s,2H), 6.55(s,2H),6.61-6.72(m,4H),7.08(t,lH),7.40-7.45 (m,5H), 7.58(d,lH), 7.99(d,lH),8.07(s,lH).
Example 52
3-{3- [ 1 - (3-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000054_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(3- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.07(s,lH), 7.90(d,lH), 7.56(d,lH), 7.26-7.50(m,10H), 7.09(t,lH), 6.66-6.70(m,2H), 6.45(d,lH), 4.98(s,2H). Example 53
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000054_0003
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fiuoro-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester. Ή NMR (300Hz, CDC13): 5ppm
4.97(s,2H),6.26(dd,lH),6.55(dd,2H),6.77-6.80(m,lH), 7.10(d,2H), 7.33- 7.48(m,7H),7.53(d,2H),8.01(d,lH),8.04(s,lH).
Example 54
3-{3- [ 1 - (3,5-Dichloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000055_0001
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(3,5- dichloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.96(s,2H), 6.48(d,lH), 6.65- 6.78(m,2H), 7.13 (t,2H), 7.33-7.43 (m,8H), 7.56(d,lH), 7.98(d,lH), 8.08(s,lH).
Example 55 3-{3- [ 1 - (2,3-Dichloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000055_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(2,3- dichloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.07(s,lH), 8.01(d,lH), 7.33- 7.57(m,9H), 7.22-7.26(m,lH), 7.12(t,lH), 6.75(t,lH), 6.68(d,lH), 6.56(d,lH), 4.97(s,2H).
Example 56 2-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000056_0001
The title compound was prepared in analogy to Example 44 starting from 2-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.10(d,lH), 7.32-7.48(m,l lH), 7.18(d,lH), 7.11(t,lH), 6.75(t,lH), 6.65(d,lH), 6.58(d,lH), 5.39(s,2H).
Example 57
4-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000056_0002
The title compound was prepared in analogy to Example 44 starting from 4-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.05(d,2H), 7.29-7.44(m,l lH), 7.09(t,lH), 6.72(t,lH), 7.29(d,lH), 6.59(d,lH), 4.98(s,2H), 3.89(s,3H).
Example 58
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000057_0001
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 3.49(s,3H), 4.95(s,2H), 6.10(dd,lH), 6.51(d,lH), 6.64 (dd,lH), 7.25-7.45 (m,10H),7.54(d,lH), 8.00(d,lH), 8.05(s,lH).
Example 59
6-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylm ethyl} -nicotinic acid
Figure imgf000057_0002
The title compound was prepared in analogy to Example 44 starting from 6-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- nicotinic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 5.19(s,2H), 6.56(d,lH), 6.58- 6.77(m, 2H), 7.09(t,lH), 7.28-7.44(m,10H), 8.30(d,lH), 9.26(s,lH). Example 60
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000057_0003
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-4-fiuoro-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.97(s,2H), 6.39- 6.51(m,2H), 7.25-7.45 (m,l lH), 7.53(d,lH), 7.99(d,lH), 8.00(s,lH). Example 61
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000058_0001
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-6-fiuoro-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.88(s,2H), 6.40- 6.429(m,lH), 7.08-7.10 (m,lH), 7.20(d,lH), 7.31-7.38 (m,10H), 7.42(d,lH),7.90(d,lH), 7.94(s,lH).
Example 62 3-{3-[l-(2-Methylsulfanyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000058_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(2- methylsulfanyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 2.31(s,3H), 5.00(dd,2H), 6.04(d,lH), 6.63 -6.64 (m,2H), 7.07(t,lH), 7.26-7.30 (m,2H), 7.33- 7.46(m,6H),7.58-7.60(m,2H), 7.99(d,lH), 8.07(s,lH).
Example 63 3-{2-Oxo-3- [ 1 -phenyl- 1 -pyridin-3-yl-meth- (E) -ylidene] -2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000059_0001
The title compound was prepared in analogy to Example 44 starting from 3-{2-oxo-3-[l- phenyl-l-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.98(s,2H), 6.40(d,lH), 6.65 -6.68 (m,2H), 7.07(t,lH), 7.35-7.42(m,8H),7.58 (d,2H), 7.69(d,lH),7.99(d,lH), 8.04(s,lH).
Example 64
3-{3-[l-(2-Chloro-5-trifluoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3- dihydro-indol- 1 -ylmethyl}-benzoic acid
Figure imgf000059_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(2- chloro-5-trifiuoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol- l-ylmethyl}-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.06(s,lH), 8.00(d,lH), 7.40-7.67(m,10H), 7.11(t,lH), 6.66-6.72(m,2H), 5.98(d,lH), 4.89-5.06(m,2H), 3.91(s,3H).
Example 65
3-{3-[l-(3,5-Bis-trifluoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3- dihydro-indol- 1 -ylmethyl}-benzoic acid
Figure imgf000060_0001
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(3,5-bis- trifiuoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.24(s,lH), 7.95- 8.10(m,4H), 7.78-7.87(m,3H), 7.67(d,2H), 7.29-7.58(m,6H), 7.21(t,lH), 6.68-6.71(m,2H), 6.27(d,lH), 4.98(s,2H), 3.91(s,3H).
Example 66
3-{2-Oxo-3-[l-phenyl-l-(3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000060_0002
The title compound was prepared in analogy to Example 44 starting from 3-{2-oxo-3-[l- phenyl-l-(3-trifiuoromethyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.08(s,lH), 8.01(d,lH), 7.72(d,lH), 7.64-7.56(m,4H), 7.35-7.54(m,4H), 7.10(dt,lH), 6.66-6.70(m,2H), 6.33(dd,lH), 4.98(s,2H).
Example 67
3-{2-Oxo-3-[l-phenyl-l-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000061_0001
The title compound was prepared in analogy to Example 44 starting from 3-{2-oxo-3-[l- phenyl-l-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.97(s,2H), 5.17(s,2H), 6.42(d,lH), 6.64 -6.71 (m,2H), 7.08(t,lH), 7.26-7.60 (m,l 1H), 7.97(s,lH), 8.00(s,lH).
Example 68
3-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (Z) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000061_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.96(s,2H), 6.42(d,lH), 6.63 6.66 (m,2H), 7.06(t,lH),7.33-7.52(m,l lH),7.92 (d,lH), 8.01(s,lH).
Example 69
3-{3- [ 1 - (4-Chloro-phenyl) - 1 - (4-trifluoromethyl-phenyl) -meth- (Z) -ylidene] -2-oxo-2 dihydro-indol- 1 -ylmethyl}-benzoic acid
Figure imgf000061_0003
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- chloro-phenyl)-l-(4-trifiuoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.98(s,2H), 6.38(d,lH), 6.68-6.73 (m,2H), 7.08(t,lH), 7.26-7.52(m,9H), 7.72(d,2H), 8.01(d,lH), 8.08(s,lH).
Example 70
(4-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-phenoxy)-acetic acid
Figure imgf000062_0001
The title compound was prepared in analogy to Example 44 starting from (4-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- phenoxy) -acetic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.56(s,2H), 4.85(s,2H), 6.51(d,lH), 6.53-6.73(m, 2H), 6.83(d,2H), 7.08(t,lH), 7.24-7.42(m,l lH).
Example 71 3-{3- [ 1 - (4-Isopropyl-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000062_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- isopropyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 1.31(d,6H), 2.94-3.01(m,lH), 4.99(s,2H), 6.56(d,lH), 6.67(dd,2H), 7.08(t,lH),7.27(s,4H), 7.38- 7.42(m,6H),7.51(d,lH),7.99(d,lH),8.08(s,lH) Example 72
3-{3- [ 1 - (3,4-Difluoro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000063_0001
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(3,4- difiuoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.97(s,2H), 6.51(d,lH), 6.71(m,2H), 7.08-7.26(m,4H), 7.34-7.43 (m,6H), 7.56(d,lH), 8.00(d,lH), 8.05(s,lH).
Example 73 3-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -7-fluoro-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000063_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-7-fiuoro-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 5.13(s,2H),
6.32(d,lH), 6.63-6.67(m,lH), 6.82-6.89(dd,lH), 7.26-7.43 (m,10H), 7.59(d,lH),
7.99(d,lH), 8.08(s,lH).
Example 74
3-{5-Chloro-3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000064_0001
The title compound was prepared in analogy to Example 44 starting from 3-{5-chloro-3- [ 1 -(4-chloro-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 -dihydro-indol- 1 -ylmethyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 4.97(s,2H), 6.58(m,2H), 7.05 (dd,lH), 7.20(m,lH), 7.27-7.46 (m,9H), 7.52(d,lH),8.01(d,lH), 8.04(s,lH).
Example 75
3-{3- [ 1 - (2-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid
Figure imgf000064_0002
The title compound was prepared in analogy to Example 44 starting from 3-{3-[l-(2- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.06(s,lH), 7.99(d,lH), 7.50- 7.57(m,3H), 7.37-7.44(m,7H), 7.07(t,lH), 6.63-6.70(m,2H), 6.05(d,lH), 4.97(dd,2H).
Example 76 2-{3- [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-thiazole-4-carboxylic acid
Figure imgf000064_0003
The title compound was prepared in analogy to Example 44 starting from 2-{3-[l-(4- chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- thiazole-4-carboxylic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 5.27(s,2H), 6.59(d,lH), 6.78(t,lH), 6.87(d,lH), 7.15(t,lH), 7.31-7.43 (m,9H), 8.22(s,lH).
Example 77
3-[3-(4-Methyl-l-phenyl-pent-(Z)-ylidene)-2-oxo-2,3-dihydro-indol-l-ylmethyl]- benzoic acid methyl ester
Figure imgf000065_0001
To a degassed refiuxing solution of 3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]- methylj-benzoic acid methyl ester (100 mg, 0.2 mmol) and Ni(PPh3)2l2 (16 mg, 0.02 mmol) in CH2C12 (8 ml) was added 3-methylbutylzinc bromide (151 mg, 0.7 mmol) in CH2C12 (1 ml). The reaction was stirred at 40°C for 6 h and then the solution was cooled to room temperature. The resultant solution was diluted with ethyl acetate (50 ml). The organic layer was washed with aqueous HCl solution (4%, 10 ml), brine (3x10 ml). The aqueous layer was back- extracted with ethyl acetate (3x10 ml). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with petrol ether-ethyl acetate, to give 3-{3-[4-methyl-l-phenyl-pent-(Z)-ylidene]- 2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester (24 mg, 28%) as light yellow solid. ¾ NMR (300Hz, CDC13): 5ppm 0.88(d,6H), 1.43-1.55(m,2H), 1.68- 1.72(m,lH), 2.93-2.99(m,2H), 3.91(s,3H), 4.89(s,2H), 6.64 (d,lH), 7.05(t,lH), 7,15(t,lH), 7.28-7.38 (m,4H), 7.40- 7.47(m,3H),7.62(d,lH), 7.91(d,lH) , 7.95(s,lH); and 3-{3-[4- methyl-l-phenyl-pent-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester (29 mg, 33%) as light yellow solid. ¾ NMR (300Hz, CDC13): δ ppm
0.88(d,6H), 1.36-1.44(m,2H), 1.64-1.68(m,lH), 3.33-3.38(m,2H), 3.91(s,3H), 5.04(s,2H), 6.01(d,lH), 6.58-6.61(m,2H), 6.96-7.02(t, 1H), 7.26-7.29(m,2H), 7.37 (t,2H), 7.43- 7.52(m,3H), 7.93(d,lH), 8.03(s,lH).
Example 78 3-{3-[3,3-Dimethyl-l-phenyl-but-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester
Figure imgf000066_0001
The title compound was prepared in analogy to Example 77 starting from tert-butylzinc bromide (commercially available) and 3-{[(2-iodo-phenyi)-(3-phenyl-propynoyi)- amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 0.80(s,9H), 2.74(s,2H), 3.90(s,3H),5.67(s,2H), 6.98(t,lH), 7.12-7.52(m,10H), 7.93(d,lH), 8.03(s, 1H).
Example 79
3-{3- [2- (4-Chloro-phenyl) - 1 -phenyl-eth- (Z) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000066_0002
The title compound was prepared in analogy to Example 77 starting from 4-chloro- benzylzinc bromide (commercially available) and 3-{[(2-iodo-phenyl)-(3-phenyl- propynoyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDCI3): 5ppm 3.92 (s,3H), 4.73(s,2H), 5.07(s,2H), 5.99(d,lH), 6.58-6.65(m,2H), 7.08-7.20(m,7H), 7.37- 7.43(m,4H), 7.52(d,lH), 7.93(d,lH),8.06(s,lH).
Example 80
3-{3-[3,3-Dimethyl-l-phenyl-but-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester
Figure imgf000067_0001
The title compound was prepared in analogy to Example 77 starting from tert-butylzinc bromide (commercially available) and 3-{[(2-iodo-phenyi)-(3-phenyl-propynoyi)- amino]-methyl}-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 0.91(s,9H), 3.48(s,2H), 3.90(s,3H),5.03(s,2H), 6.22(d,lH), 6.56-6.62(m, 2H), 6.98(t,lH), 7.36- 7.50(m,7H), 7.92(d,lH), 8.02(s,lH).
Example 81
3-[3-(4-Methyl-l-phenyl-pent-(Z)-ylidene)-2-oxo-2,3-dihydro-indol-l-ylmethyl]- benzoic acid
Figure imgf000067_0002
3-{3-[4-Methyl-l-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester (24 mg, 0.05 mmol) was dissolved in THF (1 ml) and water (1 ml) and LiOH.H20 (14 mg, 0.33 mmol) was added in one portion. The mixture was stirred at 50°C for 16 h. The mixture was concentrated under reduced pressure and acidified to pH=3. Purification by preparative HPLC afforded 3-[3-(4-methyl-l-phenyl-pent-(Z)-ylidene)-2- oxo-2,3-dihydro-indol-l-ylmethyl] -benzoic acid 10 mg. ¾ NMR (300Hz, CDC13): δ ppm 0.88(d,6H), 1.36-1.44(m,2H), 1.64-1.68(m,lH), 3.33-3.38(m,2H), 5.04(s,2H), 6.01(d,lH), 6.58-6.61 (m,2H), 6.96-7.02(t, 1H), 7.26-7.29 (m,2H), 7.37 (t,2H), 7.43- 7.52(m,3H), 7.93(d,lH) ,8.03(s,lH). Example 82
3-{3-[l-(4-Chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000068_0001
The title compound was prepared in analogy to Example 81 starting from 3-{3-[l-(4- chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm 1.14(d,6H),3.62- 3.71(m,lH),4.577(s,2H), 5.018(s,2H), 6.82 (d,lH), 7.04(t,lH), 7.21-7.26(m,5H), 7.43(t,lH), 7.53(d,lH), 7.63(d,lH), 8.01(d,lH), 8.07(s,lH).
Example 83
3-{3-[l-(4-Fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid
Figure imgf000068_0002
But-2-ynoic acid (2-iodo-phenyl) -amide
A mixture of 2-iodo-phenylamine (10 g, 45.7 mmol) and but-2-ynoic acid (4.6 g, 54.8 mmol) in dichloromethane (50 ml) was cooled to 0°C. Then 1,3-dicyclohexylcarbodiimide (14 g, 68.6 mmol) was added into. After stirring for 3 hours at room temperature, the mixture was washed with water (20 ml). The organic layer was dried over sodium sulfate and concentrated to give the crude product but-2-ynoic acid (2-iodo-phenyl)-amide (13.0 g, 100%) as yellow solid which was used in next step without purification. MS calcd. for CioHJNO 285.1, obsd. (ESP) [(M+H) +] 286.0.
3-{[(2-Iodo-phenyl)-(l-oxo-but-2-ynyl)-amino]-methyl}-benzoic acid methyl ester A mixture of but-2-ynoic acid (2-iodo-phenyl)-amide (2.85 g, 10 mmol) and cesium carbonate (4.89 g, 15 mmol) in DMF (20 ml) was stirred for 10 minutes. 3-bromomethyl- benzoic acid methyl ester (2.52 g, 11 mmol) was added. Then the mixture was stirred for 12 hours at room temperature. After removal of solids, the filtrate was treated with water and extracted with ether. The organic layer was dried over sodium sulfate and
concentrated to give the residue which was purified by flash chromatography, eluting with ethyl acetate / hexane = 1:4 to afford the product 3-{[(2-iodo-phenyl)-(l-oxo-but-2-ynyi)- amino] -methylj-benzoic acid methyl ester as yellow solid (3.03, 70%). MS calcd. for C19H1JNO3 433.3, obsd. (ESP) [(M+H) +] 434.1.
3-{3-[l-(4-Fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester
A mixture of 3-{[(2-iodo-phenyl)-(l-oxo-but-2-ynyl)-amino]-methyl}-benzoic acid methyl ester (0.5 g, 1.15 mmol), 4-fiuorophenylboronic acid (0.32 g, 2.3 mmol), tetrakis (triphenylphosphine) palladium (0.13 g, 0.115 mmol) and copper thiophene-2-carboxylic acid (0.46 g, 2.42 mmol) in THF was stirred for 5 hours at 60°C. After removal of solvent, the residue was purified by flash chromatography, eluting with ethyl acetate / hexane = 1:5 to afford the product 3-{3-[l-(4-fiuoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester (0.28 g, 60%) as a yellow solid. MS calcd. for
C25H20FNO3 401.4, obsd. (ESF) [(M+H) +] 402.2.
3-{3-[l-(4-Fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid
A solution of 3-{3-[l-(4-fiuoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester (0.33 g, 0.82 mmol) was dissolved in THF 5 ml. Then a solution of lithium hydroxide (0.35 g, 8.2 mmol) in water (2.0 ml) was added. After stirring for 12 hours, the solvent was removed under reduced pressure. The residue was dissolved in 2 ml DMF for prepared HPLC to give 3-{3-[l-(4-fiuoro-phenyl)-ethylidene]-
2- oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid as yellow powder (100 mg). ¾ NMR (400 MHz, DMSO-de) δ ppm 2.78 (s, 3 H) 5.06 (s, 2 H) 6.08 (d, /=7.83 Hz, 1 H) 6.68 (t,
/=7.45 Hz, 1 H) 6.92 (d, /=7.83 Hz, 1 H) 7.11 (t, /=7.45 Hz, 1 H) 7.38 (t, /=8.84 Hz, 2 H) 7.43 - 7.51 (m, 1 H) 7.46 (dd, /=8.72, 5.68 Hz, 2 H) 7.60 (d, /=7.58 Hz, 1 H) 7.85 (d, /=7.83 Hz, 1 H) 7.92 (s, 1 H) 13.03 (s, 1H). MS calcd. for C24Hi8FN03 387.4, obsd. (ESF)
[(M+H)+] 388.2. Example 84
3- {3-[l-(4-Chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid methyl ester
Figure imgf000070_0001
1 -Iodo-2-isocyanato-benzene
A solution of 2-iodo-phenylamine (30 g, 0.14 mol) in dichloromethane (800 ml) was added triphosgene (14.6 g, 49.3 mmol) and saturated sodium bicarbonate (544 ml) at 0°C. The resulted mixture was stirred for 4 hours. The organic layer washed with brine (200 ml) and dried over sodium sulfate. After removal of solvent, the crude product l-iodo-2- isocyanato-benzene (32.3 g, 96%) as yellow oil was obtained which was used in next step without purification.
4-Methyl-pent-2-ynoic acid (2-iodo-phenyl) -amide 3-Methyl-but-l-yne (11 g, 0.16 mol) in THF (100 ml) was added n-BuLi (2.5M in hexane) (59 ml, 0.15 mol) at 0°C. The resulted mixture was stirred for 30 minutes. Then a solution of l-iodo-2-isocyanato-benzene (33 g, 0.14 mol) in THF (100 ml) was dropped into. After stirring for 2 hours at 0°C, the mixture was treated with brine (100 ml), extracted with ether (200 ml). The organic layer was dried over sodium sulfate and concentrated to give the crude product 4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (38 g, 90%) as yellow oil which was used in next step without purification. MS calcd. for Ci2Hi2INO 313.1, obsd. (ESI+) [(M+H) +] 314.0.
3-{[(2-Iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester A mixture of 4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (21 g, 67.1 mmol) and cesium carbonate (33.0 g, 100.7 mmol) in DMF (170 ml) was stirred for 10 minutes. 3- bromomethyl-benzoic acid methyl ester (16.9 g, 73.8 mmol) was added. Then the mixture was stirred for 12 hours at room temperature. After removal of the solids, the filtrate was treated with water and extracted with ether. The organic layer was dried over sodium sulfate and concentrated to give the residue which was purified by flash chromatography, eluting with ethyl acetate / hexane = 1:4 to afford the product 3-{[(2-iodo-phenyl)-(4- methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester as yellow solid (15.9 g, 51%). MS calcd. for C21H20CINO3 461.3, obsd. (ESP) [(M+H) +] 461.9. 3-{3-[l-(4-Chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid methyl ester
A mixture of 3-{[(2-iodo-phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester (0.93 g, 2.02 mmol), 4-chlorophenylboronic acid (0.63 g, 4.04 mmol), triphenylphosphine (53 mg, 0.202 mmol), palladium acetate (23 mg, 0.10 mmol) and cesium fluoride (0.92 g, 6.06 mmol) in THF (15 ml) was stirred for 3 hours at 60°C. After removal of solvent, the residue was purified by flash chromatography, eluting with ethyl acetate / hexane = 1:5 to afford the product 3-{3-[l-(4-chloro-phenyl)-2-methyl- propylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester (0.40 g, 44%) as a yellow solid. MS calcd. for C27H24CINO3 445.5, obsd. (ESF) [(M+H) +] 446.0. ¾ NMR (400 MHz, DMSO-d6) δ ppm 1.10 (d, /=6.82 Hz, 6 H) 3.91 (s, 3 H) 4.99 (dt, /=13.71, 6.92 Hz, 1 H) 5.06 (s, 2 H) 5.73 (d, 7=7.58 Hz, 1 H) 6.62 (t, 7=7.71 Hz, 1 H) 6.73 (d, 7=7.83 Hz, 1 H) 7.05 (t, 7=7.71 Hz, 1 H) 7.19 (d, 7=8.34 Hz, 2 H) 7.46 (t, 7=7.83 Hz, 1 H) 7.55 (d, 7=8.08 Hz, 3 H) 7.94 (d, 7=7.58 Hz, 1 H) 8.02 (s, 1 H) MS calcd. for C27H24CINO3 445.5, obsd. (ESI+) [(M+H) +] 446.0.
Example 85
3-{3-[2-Methyl-l-phenyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester
Figure imgf000071_0001
The title compound was prepared in analogy to Example 84 starting from phenylboronic acid (commercially available) and 3-{[(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]- methylj-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.04(s,lH),
7.94(d,lH), 7.48-7.53(m,3H), 7.39(t,lH), 7.15(dd,2H), 6.99(t,lH), 6.59-6.61(d,lH), 6.55(t,lH), 5.59(d,2H), 5.00-5.05(m,3H), 3.97(s,3H), l.l l(s,3H), 1.09(s,3H).
Example 86
3-{3-[l-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid methyl ester
Figure imgf000072_0001
The title compound was prepared in analogy to Example 84 starting from 4-acetyl- phenylboronic acid (commercially available) and 3-{[(2-iodo phenyl)-(4-methyl-pent-2- ynoyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.03- 8.11(m,4H), 7.94(d,lH), 7.71(d,lH), 7.52(d,lH), 7.40(t,lH), 7.29(d,2H), 7.00(t,lH), 6.61(d,lH), 6.54(t,lH), 5.61(d,H), 5.02-5.07(m,3H), 3.90(s,3H), 2.70(s,3H), 1.19(d,3H), 1.17(d,3H).
Example 87
3-{3-[l-(4-Chloro-phenyl)-l-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid methyl ester
Figure imgf000072_0002
The title compound was prepared in analogy to Example 84 starting from 4-chloro- phenylboronic acid (commercially available) and 3-{[(3-cyclohexyl-propynoyl)-(2-iodo- phenyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (CDCi3,300MHz) 5ppm 8.02(s,lH), 7.93(d,lH), 7.47-7.51(m,13H), 7.39(t,lH), 7.10(d,2H), 7.01(t,lH), 6.59- 6.63(m,2H), 5.71(d,2H), 5.02(s,2H), 4.62(t,lH), 3.91(s,3H), 1.44-1.76(m,6H), 1.01- 1.18(m,4H).
Example 88
3-{3-[2-Methyl-l-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000073_0001
The title compound was prepared in analogy to Example 84 starting from 4- trifiuoromethyl-phenylboronic acid (commercially available) and 3-{[(2-iodo phenyl)-(4- methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR
(DMSO,300MHz) 5ppm 7.90(s,lH), 7.79-7.86(m,2H), 7.58(d,lH), 7.48(t,lH), 7.42(d,lH), 7.09(t,lH), 7.00(d,lH), 6.89(d,lH), 6.65(t,lH), 5.65(d,lH), 5.03(s,2H), 4.84-4.93(m,lH), 3.57(s,3H), 0.96-1.06(dd,6H).
Example 89
3-{3-[l-(4-Chloro-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000073_0002
The title compound was prepared in analogy to Example 84 starting from 4-chloro- phenylboronic acid (commercially available) and 3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)- (2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (400 MHz, DMSO- d6) 5ppm 1.30 (s, 6 H) 3.83 (s, 3 H) 5.14 (s, 2 H) 5.43 (d, J=7.58 Hz, 1 H) 6.68 (t, J=7.58 Hz, 1 H) 7.01 (d, J=7.83 Hz, 1 H) 7.12 (t, J=7.45 Hz, 1 H) 7.27 (d, J=8.34 Hz, 2 H) 7.51 (t, J=7.71 Hz, 1 H) 7.58 - 7.65 (m, 4 H) 7.87 (d, J=7.58 Hz, 1 H) 7.97 (s, 1 H).
Example 90
3-{3-[l-(4-Cyano-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester
Figure imgf000074_0001
The title compound was prepared in analogy to Example 84 starting from 4-cyano- phenylboronic acid (commercially available) and 3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)- (2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (400 MHz, DMSO- d6) 5ppm 1.33 (s, 6 H) 3.85 (s, 3 H) 5.15 (s, 2 H) 5.35 (d, J=7.83 Hz, 1 H) 6.68 (t, J=7.71 Hz, 1 H) 7.03 (d, J=7.83 Hz, 1 H) 7.15 (t, J=7.71 Hz, 1 H) 7.48 - 7.55 (m, 1 H) 7.52 (d, J=7.58
Hz, 3 H) 7.62 (d, J=7.83 Hz, 1 H) 7.89 (d, J=7.83 Hz, 1 H) 7.99 (s, 1 H) 8.05 (d, J=8.34 Hz, 2 H).
Example 91 3-{3- [ 1 - (4-Chloro-phenyl) -2,2-dimethyl-prop- (Z) -ylidene] -2-oxo-2,3-dihydro-indol- 1 - ylmethyl}-benzoic acid methyl ester
Figure imgf000074_0002
The title compound was prepared in analogy to Example 84 starting from 4-chloro- phenylboronic acid (commercially available) and 3-{[(4,4-dimethyl-pent-2-ynoyl)-(2- iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (400 MHz, MeOD) 5ppm 1.38 (s, 9 H) 3.86 (s, 3 H) 4.83 (d, 2 H) 6.81 (d, J=7.83 Hz, 1 H) 6.99(d, J=7.83 Hz, 2 H) 7.10 (t, J=7.58 Hz, 1 H) 7.22 (t, J=7.71 Hz, 1 H) 7.33 - 7.42 (m, 4 H) 7.84 - 7.88 (m, 2 H) 7.93 (d, J=7.83 Hz, 1 H).
Example 92 3-{3-[l-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid methyl ester
Figure imgf000075_0001
The title compound was prepared in analogy to Example 84 starting from 4-cyano- phenylboronic acid (commercially available) and 3-{[(4,4-dimethyl-pent-2-ynoyi)-(2- iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (400 MHz, DMSO-d6) 5ppm 1.35 (s, 9 H) 3.84 (s, 3 H) 5.07 (s, 2 H) 5.19 (d, J=7.83 Hz, 1 H) 6.56 (t, J=7.71 Hz, 1 H) 6.88 (d, J=7.83 Hz, 1 H) 7.06 (t, J=7.71 Hz, 1 H) 7.42 (d, J=8.08 Hz, 2 H) 7.50 (t, J=7.71 Hz, 1 H) 7.59 (d, J=7.58 Hz, 1 H) 7.87 (d, J=7.58 Hz, 1 H) 7.95 - 8.05 (m, 3 H).
Example 93
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid methyl ester
Figure imgf000075_0002
The title compound was prepared in analogy to Example 84 starting from 4-chloro- phenylboronic acid (commercially available) and 3-{[(4,4-dimethyl-pent-2-ynoyl)-(2- iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. ¾ NMR (400 MHz, DMSO-d6) 5ppm 1.36 (s, 9 H) 3.84 (s, 3 H) 5.07 (s, 2 H) 5.30 (d, J=7.83 Hz, 1 H) 6.57 (t, J=7.83 Hz, 1 H) 6.88 (d, J=7.83 Hz, 1 H) 7.05 (t, J=7.71 Hz, 1 H) 7.21 (d, J=8.08 Hz, 2 H) 7.51 (t, J=7.71 Hz, 1 H) 7.57 - 7.64 (m, 2 H) 7.87 (d, J=7.58 Hz, 1 H) 7.97 (s, 1 H).
Example 94
3-{3-[l-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000076_0001
A solution of 3-{3-[l-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol- l-ylmethyl}-benzoic acid methyl ester (0.40 g, 0.90 mmol) was dissolved in THF 15 ml. Then a solution of lithium hydroxide (0.38 g, 9.0 mmol) in water (3.0 ml) was added. After stirring for 12 hours, the solvent was removed under reduced pressure. The residue was dissolved in 2 ml DMF for prepared HPLC to give 3-{3-[l-(4-chloro-phenyl)-2-methyl- propylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid as yellow powder (200 mg). ¾ NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, 7=6.82 Hz, 6 H) 4.90 - 4.99 (m, 1 H) 5.05 (s, 2 H) 5.59 (d, /=7.83 Hz, 1 H) 6.64 (t, /=7.71 Hz, 1 H) 6.91 (d, /=7.83 Hz, 1 H) 7.10 (t, /=7.71 Hz, 1 H) 7.27 (d, /=8.34Hz, 2 H) 7.49 (t, /=7.58 Hz, 1 H) 7.63 (d, /=8.34 Hz, 2 H) 7.59 (d, /=7.58 Hz, 1 H) 7.85 (d, 7=7.58 Hz, 1H) 7.92 (s, 1 H) 13.05 (s, 1 H). MS calcd. for C26H22CINO3 431.5, obsd. (ESP) [(M+H)+] 432.0.
Example 95
3-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000076_0002
The title compound was prepared in analogy to Example 94 starting from 3-{3-[l-(4- cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydroindol-l-ylmethyl} benzoic acid meth yl ester. ¾ NMR (400 MHz, DMSO-d6) 5ppm 1.01 (d, J=6.82 Hz, 6 H) 4.91 - 5.00 (m, 1 H) 5.05 (s, 2 H) 5.50 (d, J=7.83 Hz, 1 H) 6.64 (t, J=7.58 Hz, 1 H) 6.93 (d, J=7.83 Hz, 1 H) 7.11 (t, J=7.58 Hz, 1 H) 7.48 (d, J=7.58 Hz, 3 H) 7.60 (d, J=7.58 Hz, 1 H) 7.85 (d, J=7.33 Hz, 1 H) 7.93 (s, 1 H) 8.05 (d, J=8.08 Hz, 2 H) 13.06 (br.s., 1 H).
Example 96 6-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihyd:
ylmethyl}-pyridine-2-carboxylic acid
Figure imgf000077_0001
The title compound was prepared in analogy to Example 94 starting from 6-{3-[l-(4- chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-lylmethyl}- pyridine-2-carboxylic acid methyl ester. ¾ NMR (400 MHz, MeOD) 5ppm 1.06 (d, 6 H) 4.92 - 5.01 (m, 1 H) 5.23 (s, 2 H) 5.74 (d, 1 H) 6.64 (t, 1H) 6.87 (d, 1 H) 7.08 (t, 1 H) 7.22 (d, 2 H) 7.45 (d, 1 H) 7.59 (d, 2 H) 7.95 (t, 1 H) 8.09 (d, 1 H).
Example 97 6-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid
Figure imgf000077_0002
The title compound was prepared in analogy to Example 94 starting from 6-{3-[l-(4- cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydroindol-l-ylmethyl}- pyridine-2-carboxylic acid methyl ester. ¾ NMR (400 MHz, MeOD) 5ppm 1.06 (d, 6 H) 4.95 - 5.08 (m, 1 H) 5.25 (s, 2 H) 5.64 (d, 1 H) 6.63 (t, 1H) 6.89 (d, 1 H) 7.09 (t, 1 H) 7.46 (d, 3 H) 7.90 - 8.00 (m, 3 H) 8.09 (d, 1 H).
Example 98
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000078_0001
The title compound was prepared in analogy to Example 94 starting from 3-{3-[l-(4- chloro-phenyl)-2,2-dimethyl-prop-(Z)ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (400 MHz, DMSO-d6) 5ppm 1.32 (s, 9 H) 4.86 (s, 2 H) 6.95 (d, J=7.58 Hz, 1 H) 7.04 (d, J=8.59 Hz, 2 H) 7.13 (t, 1 H) 7.29 (t, 1 H) 7.38 - 7.42 (m, 2 H) 7.44 (d, J=5.05 Hz, 2 H) 7.77 - 7.84 (m, 2 H) 7.88 (d, J=7.83 Hz, 1 H) 13.01 (s, 1 H).
Example 99
3-{3-[l-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000078_0002
The title compound was prepared in analogy to Example 94 starting from 3-{3-[l-(4- cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-lylmethyl}- benzoic acid methyl ester. ¾ NMR (400 MHz, DMSO-d6) 5ppm 1.35 (s, 9 H) 5.06 (s, 2 H) 5.19 (d, J=7.83 Hz, 1 H) 6.57 (t, J=7.45 Hz, 1 H) 6.89 (d, J=7.58 Hz, 1 H) 7.07 (t, J=7.45 Hz, 1 H) 7.41 - 7.51 (m, 3 H) 7.56 (d, 1 H) 7.84 (d, J=7.58 Hz, 1 H) 7.93 (s, 1 H) 8.03 (d, J=8.34 Hz, 2 H).
Example 100
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000079_0001
The title compound was prepared in analogy to Example 94 starting from 3-{3-[l-(4- chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (400 MHz, DMSO-d6) 5ppm 1.35 (s, 9 H) 5.06 (s, 2 H) 5.30 (d, J=7.83 Hz, 1 H) 6.57 (t, 1 H) 6.88 (d, J=7.83 Hz, 1 H) 7.06 (t, 1 H) 7.22 (d, J=8.08 Hz, 2 H) 7.49 (t, 1 H) 7.54 - 7.63 (m, 3 H) 7.84 (d, 1 H) 7.93 (s, 1 H) 12.97 (s, 1 H).
Example 101
3-{3-[l-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000079_0002
The title compound was prepared in analogy to Example 94 starting from 3-{3-[l-(4- fiuoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (400 MHz, DMSO-d6) 5ppm 1.01 (d, J=6.82 Hz, 6 H) 4.87 - 4.99 (m, 1 H) 5.05 (s, 2 H) 5.54 (d, J=7.83 Hz, 1 H) 6.63 (t, J=7.33 Hz, 1 H) 6.90 (d, J=7.58 Hz, 1 H) 7.09 (d, J=1.01 Hz, 1 H) 7.24 - 7.31 (m, 2 H) 7.40 (t, J=8.84 Hz, 2 H) 7.49 (t, J=7.58 Hz, 1 H) 7.59 (d, J=7.58 Hz, 1 H) 7.85 (d, J=7.83 Hz, 1 H) 7.92 (s, 1 H) 13.03 (s, 1 H).
Example 102
6-{3-[l-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid
Figure imgf000080_0001
The title compound was prepared in analogy to Example 94 starting from 6-{3-[l-(4- fiuoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl} pyridine-2-carbo xylic acid methyl ester. ¾ NMR (400 MHz, DMSO-d6) 5ppm 1.01 (d, J=6.82 Hz, 6 H) 4.86 - 5.00 (m, 1 H) 5.16 (br. s., 2 H) 5.56 (d, J=7.83 Hz, 1 H) 6.63 (t, J=7.71 Hz, 1 H) 6.85 (d, J=7.33 Hz, 1 H) 7.06 (t, J=7.58 Hz, 1 H) 7.29 (d, J=5.56 Hz, 2 H) 7.27 (d, J=5.81 Hz, 1 H) 7.41 (t, J=8.72 Hz, 2 H) 7.81 - 7.98 (m, 2 H).
Example 103
3-{3-[2-Methyl-l-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid
Figure imgf000080_0002
The title compound was prepared in analogy to Example 94 starting from 3-{3-[2-methyl- l-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester. ¾ NMR (400 MHz, MeOD) 5ppm 1.13 (t, J=7.71 Hz, 6 H) 5.01 - 5.14 (m, 1 H) 5.10 (s, 2 H) 5.59 (d, J=7.83 Hz, 1 H) 6.62 (t, J=7.71 Hz, 1 H) 6.83 (d, J=7.83 Hz, 1 H) 7.11 (t, J=7.71 Hz, 1 H) 7.47 (t, J=7.71 Hz, 1 H) 7.59 (d, J=7.58 Hz, 1 H) 7.84 (br. s., 1 H) 7.93 - 8.05 (m, 2 H) 7.96 (s, 1 H) 8.58 (br. s., 1 H) 8.85 (br. s., 1 H).
Example 104
3-{3-[l-(4-Chloro-phenyl)-l-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000081_0001
The title compound was prepared in analogy to Example 94 starting from 3-{3-[l-(4- chloro-phenyl)-l-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.09(s,lH), 8.02(d,lH), 7.57(d,lH), 7.41-7.50(m,3H), 7.11(d,2H), 7.03(t,lH), 6.60-6.64(m,2H), 5.73(d,lH), 5.05(s,2H), 4.63(m,lH), 1.44-1.8 l(m,6H), 1.01-1.18(m,4H).
Example 105
3-{3-[2-Methyl-l-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid
Figure imgf000081_0002
The title compound was prepared in analogy to Example 94 starting from 3-{3-[2-methyl- l-(4-trifiuoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.08(s,lH), 8.00(d,lH), 7.77(d,2H), 7.58(d,lH), 7.44(t,lH), 7.31(d,2H), 7.03(t,lH), 6.63(d,lH), 6.58(t,lH), 5.58(d,lH), 5.04-5.08(m,3H), 1.16(s,3H), 1.13(s,lH).
Example 106
3-{3-[2-Methyl-l-thiophen-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000081_0003
The title compound was prepared in analogy to Example 94 starting from 3-{3-[2-methyl- l-thiophen-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.08(s,lH), 8.01(d,lH), 7.77(d,2H), 7.58(d,lH), 7.44(t,lH), 7.31(d,2H), 7.03(t,lH), 6.63(d,lH), 6.58(t,lH), 5.58(d,lH), 5.04- 5.08(m,3H), 1.10(s,3H), 1.07(s,3H).
Example 107
3-{5-Chloro-3-[2-methyl-l-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3- dihydro-indol- 1 -ylmethyl}-benzoic acid
Figure imgf000082_0001
The title compound was prepared in analogy to Example 94 starting from 3-{5-chloro-3- [2-methyl-l-(4-trifiuoromethyl phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester. ¾ NMR (300Hz, CDC13): 5ppm l.l l(d,6H), 5.00- 5.04 (m,lH), 5.01(s,2H), 5.40(d,lH), 6.51 (d,lH), 6.98(dd,lH), 7.28 (d,2H), 7.42(t,lH), 7.56(m,lH), 7.81(d,2H), 8.01-8.04m,2H).
Example 108
3-{3-[l-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoic acid
Figure imgf000082_0002
The title compound was prepared in analogy to Example 94 starting from 3-{3-[l-(4- acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester. ¾ NMR (CDCl3,300MHz) 5ppm 8.00-8.12(m,3H), 7.72(d,lH), 7.57(d,lH), 7.44(t,lH), 7.29(d,2H), 7.02(t,lH), 6.62(d,lH), 6.55(t,lH), 5.63(d,2H), 5.04(m,3H), 2.70(s,3H), 1.10(s,3H), 1.08(s,3H). Example 109
N-(3-{3-[l-(4-Chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-benzoyl)-methanesulfonamide
Figure imgf000083_0001
A mixture of 3-{3-[l-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid (0.22 g, 0.51 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.20 g, 1.02 mmol), methylsulfonamide (97 mg, 1.02 mmol), DMAP (12.2 mg, 0.10 mmol) in dichloromethane (20 ml) was stirred for 72 hours. The organic solution washed with brine (10 ml) then dried over sodium sulfate. After removal of solvent, the residue was dissolved in 2 ml DMF for prepared HPLC to give the product N-(3-{3-[l-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol- l-ylmethyl}-benzoyl)-methanesulfonamide (100 mg, 38%) as yellow solid. ¾ NMR (400 MHz, DMSO-de) δ ppml.21 (d, /=6.82 Hz, 6 H) 3.50 (s, 3 H) 5.00 - 5.12 (m, 1 H) 5.17 (s, 2H) 5.52 (s, 1 H) 5.84 (d, /=7.83 Hz, 1 H) 6.75 (t, /=7.83 Hz, 1 H) 6.85 (d, /=7.83 Hz, 1 H) 7.17 (t, /=7.20 Hz, 1 H) 7.28 (d, /=8.59 Hz, 2 H) 7.60 (t, /=7.71 Hz, 1 H) 7.65 (d, /=8.34 Hz, 2 H) 7.70 (d, /=7.83 Hz, 1H) 7.94 (d, /=7.83 Hz, 1 H) 8.02 (s, 1 H). MS calcd. for
C27H25CIN2O4S 508.5, obsd. (ESP) [(M+H)+] 509.2.
Example 110
N- (3-{3- [ 1 - (4-Chloro-phenyl) -2,2-dimethyl-prop- (E) -ylidene] -2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoyl)-methanesulfonamide
Figure imgf000083_0002
The title compound was prepared in analogy to Example 109 starting from 3-{3-[l-(4- chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid. ¾ NMR (400 MHz, MeOD) δρρηι 1.44 (s, 9 H) 3.11 (s, 3 H) 5.05 (s, 2 H) 5.41 (d, J=7.83 Hz, 1 H) 6.52 (t, 1 H) 6.74 (d, J=7.58 Hz, 1 H) 7.00 (t, 1 H) 7.12 - 7.21 (m, 2 H) 7.30 - 7.39 (m, 2 H) 7.51 - 7.60 (m, 2 H) 7.89 - 7.97 (m, 1 H) 8.04 (s, 1 H).
Example 111 N- (3-{3- [ 1 - (4-Chloro-phenyl) -2,2-dimethyl-prop- (Z) -ylidene] -2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoyl)-methanesulfonamide
Figure imgf000084_0001
The title compound was prepared in analogy to Example 109 starting from 3-{3-[l-(4- chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid. ¾ NMR (400 MHz, DMSO-d6) 5ppm 1.32 (s, 9 H) 3.34 (s, 3 H) 4.84 (s, 2 H) 6.93 (d, J=7.83 Hz, 1 H) 7.04 (d, J=8.34 Hz, 2 H) 7.12 (t, J=7.33 Hz, 1 H) 7.27 (t, J=7.45 Hz, 1 H) 7.37 - 7.47 (m, 4 H) 7.78 - 7.85 (m, 2 H) 7.88 (d, J=8.08 Hz, 1 H).
Example 112
Evaluation of AMPK modulator by analysis of AMPK and ACC phosphorylation This method evaluates endogenous expression and phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase (ACC) in L6 cell line using Western blot analysis. It is used to determine the potency and efficacy of small molecular AMPK modulators.
L6 cells (ATCC) are cultured and maintained at DMEM (high glucose, Gibco, BRL) with 10% fetal bovine serum (FBS, Hyclone). In an assay, cells are plated at 3x106 per plate in 10 ml on a 10 cm dish and they reach subconfiuent of 70-80% within 24 hrs. The cells are serum starved overnight prior to be treated with an AMPK modulator. The compound concentration typically ranges from 0 to 100 μΜ and treat the cells for 1-4 hrs. Once the incubation is completed, the medium is aspirated and the cell layer is gently rinsed with 2 ml of ice-cold PBS. 500 μΐ of lysis buffer containing 150 mM NaCl, 5 mM EDTA, 2 mM EGTA, 25 mM NaF, 2 mM Na3V04, 1 mg/ml of Pefabloc, 1% Triton X-100, and a Roche Complete Protease Inhibitor Tablet is added and incubated on ice for 10 min. The cell lysate is harvested and subsequently centrifugated at 12,000 rpm for 10 min at 4°C. The supernatant is saved and its protein concentration is determined using Quick Start Bradford protein quantification kit (Bio-Rad). 40 μg is loaded for 7.5% SDS-PAGE analysis and subsequently blotted to PVDF membrane following a standard procedure. The membrane is treated with a blocking buffer (5% nonfat milk) for 1 h at room
temperature in agitation. The levels of phospho-AMPK and phospho-ACC are
determined using phospho-AMPKa(Thrl72)(40H9) rabbit mAb (Cell Signaling) and phospho-acetyl CoA carboxylase(Ser79) antibody (Cell Signaling) as primary antibodies by incubating the blot at 4°C overnight. The blots are stripped and re-probed using acetyl CoA carboxylase (C83B10) rabbit mAb (Cell signaling), AMPKa(23A3) rabbit mAb (Cell Signaling), and β-actin antibody (Cell Signaling) to determine the whole protein level of ACC, AMPK and β-actin, respectively. Each protein band in a blot is visualized via ECL Plus Western blotting detection kit (Amersham) and quantified by the scan analysis. The EC5o value, defined as an activator concentration that produces half of the maximal activation effect, and Emax, defined as the maximal activation effect at the infinite activator concentration, are determined semi-quantitatively and recorded. All the compounds of formula (I) are active in the foregoing AMPK and ACC
phosphorylation assay.
Example 113
Scintillation Proximity Assay
Preparation of Enzymes Recombinant human AMPK αΐβΐγΐ, α2β1γ1 or AMPK a subunit truncations al(l-335), al(l-394) and a2(l-394) were constructed, expressed and purified as described previously (Pang, T., Zhang, Z.S., Gu, M., Qiu, B.Y., Yu, L.F., Cao, P.R., Shao, W., Su, M.B., Li, J.Y., Nan, F.J., and Li, J. (2008)). Rat liver AMPK heterotrimer enzyme was obtained from Upstate (Billerica, MA, U.S.A.). Scintillation Proximity Assay
Before the Scintillation Proximity Assay (SPA) assay, 200 nM recombinant AMPK proteins (αΐβΐγΐ, α2β1γ1, al(l-335), al(l-394) or α2(1-394)) were fully
phosphorylated as described previously (Pang et al., 2008). SPA reactions were performed in 96-well plates at a final volume of 50 μΐ containing 20 mM Tris-HCl pH 7.5, 5 mM MgCl2, 1 mM DTT, 2 μΜ biotin-SAMS, 2 μΜ ATP,0.2 μα/well [γ-33Ρ] ATP, and various amount of activator. Reactions were initiated by the addition of 50 nM recombinant AMPK proteins to the reaction solutions and incubated at 30°C for 2 hr. After that, reactions were terminated by the addition of 40 μΐ stop solution containing 80 μg streptavidin-coated SPA beads per well, 50 mM EDTA, 0.1% Triton X-100 in PBS, pH 7.5 and incubated for 1 hr. Finally, a 160 ul suspension solution containing 2.4 M CsCl, 50 mM EDTA, and 0.1% Triton X-100 in PBS (pH 7.5) was added to the reaction solution to suspend SPA beads completely. SPA signals were determined with a Wallac MicroBeta plate counter (PerkinElmer) 30 min later for calculation of the amount of product formed. The amount of products formed in 2 hr was plotted against activator concentrations to determine the effective concentration of the activator (EC50) required for 50% of maximal enzyme activity.
Compounds as described above have EC50 values between 0.5 uM and 50 uM, preferred compounds have EC50 values between 0.5 uM and 10 uM, particularly preferred compounds have EC50 values between 0.5 uM and 1 uM. These results have been obtained by using the foregoing Scintillation Proximity Assay (uM means microMolar).
The EC50 of representative compounds of formula (I) are reported in the following table.
EC50
Example No. (uM)
1 2.21
2 1.49
3 5.61
4 5.25
5 2.3
6 1.51
7 1.54
8 6.47
9 2.16
10 4.44
11 3.11
12 5.34
13 1.86
14 4.34
15 2.47
16 1.53
17 2.34
18 5.66
19 1
20 1.76
21 6.07
22 4.13
23 6.97
24 4.82
25 2.73
26 1.25 27 2.73
28 0.8
29 2.36
30 1.65
31 0.77
32 10.52
33 5.56
34 1.8
35 2.95
36 3.69
37 4.49
38 2.91
39 1.57
41 4.51
42 4.5
43 3.23
44 1.21
45 1.89
46 4.02
47 2.38
48 3.15
49 1.75
50 5.89
51 1.42
52 6.55
53 5.89
54 5.14
55 2.94
56 4.24
57 2.17
58 4.87
59 5.19
60 1.24
61 4.93
62 2.33
63 3.24
64 6.63
65 3.41
66 2.44
67 1.27
68 2.12
69 2.2
70 4.96 71 4.02
72 3.3
73 5.14
74 3.17
75 1.84
76 5.14
77 2.58
78 1.6
79 1.69
80 5.8
81 4.74
82 1.6
85 4.9
86 7.88
87 10.65
88 2.59
104 4.63
105 2.95
106 1.61
107 0.66
108 3.25
Example A
A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
Per tablet
Active ingredient 200 mg
Microcrystalline cellulose 155 mg
Corn starch 25 mg
Talc 25 mg
Hydroxypropylmethylcellulose 20 mg
425 mg
Example B
A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule
Active ingredient 100.0 mg
Corn starch 20.0 mg
Lactose 95.0 mg Talc 4.5 mg
Magnesium stearate 0.5 mg
220.0 mg

Claims

Claims
1. A compound of formula (I)
Figure imgf000090_0001
wherein
R1 is hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy or alkylcarbonyl;
R2 is hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy or alkylcarbonyl;
R3 is hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy or alkylcarbonyl;
R4 is hydrogen, halogen, alkoxy, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy or alkylcarbonyl;
R5 is is alkyl, hydroxyalkyl, cycloalkyl, phenylalkyl, halophenylalkyl, phenyl,
substituted phenyl, thiophenyl or pyridinyl, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl;
R6 is is alkyl, hydroxyalkyl, cycloalkyl, phenylalkyl, halophenylalkyl, phenyl,
substituted phenyl, thiophenyl or pyridinyl, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl; provided that R5 and R6 are not both methoxyphenyl at the same time;
R7 is substituted phenyl, pyridinyl, substituted pyridinyl, thiazolyl, substituted
thiazolyl or carboxy, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, wherein substituted pyridinyl and substituted thiazolyl are pyridinyl and thiazolyl substituted with alkoxycarbonyl or carboxy; and provided that when one of R5 and R6 is phenyl and the other one is phenyl,
methylphenyl or alkoxyphenyl, then R7 is alkoxycarbonylphenyl; n is 0 or 1; or a pharmaceutically acceptable salt or ester thereof.
2. A compound according to claim 1, wherein R1 is hydrogen, halogen or alkoxy.
3. A compound according to claim 1 or 2, wherein R1 is hydrogen, fiuoro or chloro.
4. A compound according to any one of claims 1 to 3, wherein R2 is hydrogen, halogen or alkoxy.
5. A compound according to any one of claims 1 to 4, wherein R2 is hydrogen or
fiuoro.
6. A compound according to any one of claims 1 to 5, wherein R3 is hydrogen, halogen or alkoxy.
7. A compound according to any one of claims 1 to 6, wherein R3 is hydrogen, fiuoro, chloro or methoxy.
8. A compound according to any one of claims 1 to 7, wherein R4 is hydrogen, halogen or alkoxy.
9. A compound according to any one of claims 1 to 8, wherein R4 is hydrogen or
fiuoro.
10. A compound according to any one of claims 1 to 9, wherein R5 is alkyl,
halophenylalkyl, phenyl, substituted phenyl, thiophenyl or pyridinyl, wherein substituted phenyl is phenyl substituted with one to three substituents
independently selected from alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl.
11. A compound according to any one of claims 1 to 10, wherein R5 is halophenyl or cyanophenyl.
12. A compound according to any one of claims 1 to 11, wherein R5 is chlorophenyl or cyanophenyl.
13. A compound according to any one of claims 1 to 12, wherein R6 is alkyl,
hydroxyalkyl, cycloalkyl, phenyl or halophenyl.
14. A compound according to any one of claims 1 to 13, wherein R6 is alkyl or phenyl.
15. A compound according to any one of claims 1 to 14, wherein R6 is isopropyl or
phenyl.
16. A compound according to any one of claims 1 to 15, wherein R7 is substituted
phenyl, substituted pyridinyl, substituted thiazolyl or carboxy, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy and
alkylsulfonylaminocarbonyl, wherein substituted pyridinyl and substituted thiazolyl are pyridinyl and thiazolyl substituted with alkoxycarbonyl or carboxy.
17. A compound according to any one of claims 1 to 16, wherein R7 is carboxyphenyl, alkoxycarbonylphenyl or carboxypyridinyl.
18. A compound according to any one of claims 1 to 17, wherein R7 is carboxyphenyl, methoxycarbonylphenyl or carboxypyridinyl.
19. A compound according to anyone of claims 1 to 18 selected from
3-{2-Oxo-3-[l-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-l-yl}-benzoic acid ethyl ester;
(3-{2-Oxo-3-[l-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-l-yl}-phenyl)-acetic acid methyl ester;
2- Methyl-5-{2-oxo-3-[l-phenyl-eth-(E)-ylidene]-2,3-dihydro-indol-l-yl}-benzoic acid methyl ester;
[2-Oxo-3-(l-phenyl-ethylidene)-2, 3 -dihydro-indol-l-yl] -acetic acid;
3- {3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-7-fiuoro-2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester; 3-(3-Benzhydrylidene-2-oxo-2,3-dihydro-indol-l-ylmethyl)-benzoic acid methyl ester;
3-{3-[l-(4-Methoxy-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol l-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[l-phenyl-l-p-tolyl-meth-(E)-ylidene]-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-(2-methoxy-phenyl)-meth-(Z)-ylidene] -2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Cyano-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{2-Oxo-3-[l -phenyl- l-(4-trifluoromethyl-phenyl)-meth-(E)-ylidene] -2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester;
3 -{3 - [ 1 -(3 -Chloro-4-fluoro-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 - dihydro-indol-l-ylmethyl}-benzoic acid methyl ester;
3-{2-Oxo-3-[l-phenyl-l-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(3,4-Difluoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(3-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid methyl ester;
3-{3-[l-(2-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3- dihydro-indol-1 -ylmethylj-benzoic acid methyl ester;
3-{3-[l-(3,5-Dichloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid methyl ester;
3 -{3 - [ 1 -(2,3 -Dichloro-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 -dihydro- indol-1 -ylmethylj-benzoic acid methyl ester; 4-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3- dihydro-indol-1 -ylmethylj-benzoic acid methyl ester;
3-{3-[l-(2-Bromo-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid methyl ester;
3-{3-[l-(2-Chloro-5-trifluoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo- 2,3-dihydro-indol-l-ylmethylJ-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3- dihydro-indol-1 -ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3- dihydro-indol-1 -ylmethylj-benzoic acid methyl ester;
3-{3-[l-(3-Bromo-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid methyl ester;
3-{3-[l-(2-Methylsulfanyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro indol-1 -ylmethylj-benzoic acid methyl ester;
3-{7-Chloro-3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo- 2,3-dihydro-indol-l-ylmethylJ-benzoic acid methyl ester;
3 -{2-Oxo-3 - [ 1 -phenyl- 1 -(3 -trifluoromethyl-phenyl) -meth-(E) -ylidene] -2,3 - dihydro-indol-1 -ylmethylj-benzoic acid methyl ester;
3-{2-Oxo-3-[l-phenyl-l-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-1 -ylmethylj-benzoic acid methyl ester;
3-{3-[l-(2-Methanesulfonyl-phenyl)-l-phenyl-meth-(E)-ylidene] -2-oxo-2,3- dihydro-indol-1 -ylmethylj-benzoic acid methyl ester;
3-{2-Oxo-3-[l-phenyl-l-thiophen-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid methyl ester; 3-{3-[l -(4-Chloro-phenyl)- l-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo- 2,3-dihydro-indol-l-ylmethyl}-benzoic acid methyl ester;
(4-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-
1- ylmethyl}-phenoxy)-acetic acid ethyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethyl}-N-isopropyl-benzamide;
6-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethyl} -nicotinic acid methyl ester;
2- {3-[l -(4-Chloro-phenyl)- l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethyl}-thiazole-4-carboxylic acid ethyl ester;
3 - [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] - 1 - (4-methoxy-benzyl) - 1 ,3 - dihydro-indol-2-one;
3 - [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] - 1 - (3 ,4,5 -trihydroxy-benzyl) - l,3-dihydro-indol-2-one;
3 - [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (Z) -ylidene] - 1 - (3 ,4,5 -trihydroxy-benzyl) - l,3-dihydro-indol-2-one;
3 - [ 1 - (4-Chloro-phenyl) - 1 -phenyl-meth- (E) -ylidene] - 1 - (4-hydroxy-benzyl) - 1 ,3 - dihydro-indol-2-one;
3- {3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Fluoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Methoxy-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol l-ylmethyl}-benzoic acid;
3-{3-[l -(4-Chloro-phenyl)- 1- (2 -methoxy-phenyl)-meth-(Z) -ylidene] -2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
3-{2-Oxo-3-[l -phenyl- l-(4-trifluoromethyl-phenyl)-meth-(E) -ylidene] -2,3- dihydro-indol- 1 -ylmethylj-benzoic acid; 3-{2-Oxo-3-[l -phenyl- l-(2-trifluoromethoxy-phenyl)-meth-(E)-ylidene] -2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
3 -{3 - [ 1 -(3 -Chloro-4-fluoro-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 - dihydro-indol- 1 -ylmethylj-benzoic acid;
3-{2-Oxo-3-[l-phenyl-l-(3,4,5-trimethoxy-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{3-[l-(3-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-fluoro-2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
3- {3-[l-(3,5-Dichloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3 -{3 - [ 1 -(2,3 -Dichloro-phenyl) - 1 -phenyl-meth-(E) -ylidene] -2-oxo-2,3 -dihydro- indol- 1 -ylmethylj-benzoic acid;
2- {3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid;
4- {3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid;
3- {3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-5-methoxy-2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
6-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj -nicotinic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-4-fluoro-2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-6-fluoro-2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
3-{3-[l-(2-Methylsulfanyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro indol-1 -ylmethylj-benzoic acid; 3-{2-Oxo-3-[l-phenyl-l-pyridin-3-yl-meth-(E)-ylidene]-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(2-Chloro-5-trifluoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo- 2,3-dihydro-indol-l-ylmethyl}-benzoic acid;
3-{3-[l-(3,5-Bis-trifluoromethyl-phenyl)-l-phenyl-meth-(E)-ylidene] -2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
3 -{2-Oxo-3 - [ 1 -phenyl- 1 -(3 -trifluoromethyl-phenyl) -meth-(E) -ylidene] -2,3 - dihydro-indol- 1 -ylmethylj-benzoic acid;
3-{2-Oxo-3-[l-phenyl-l-(4-sulfamoyl-phenyl)-meth-(E)-ylidene]-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-(4-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-2-oxo- 2,3-dihydro-indol-l-ylmethylJ-benzoic acid;
(4-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-
1- ylmethyl}-phenoxy)-acetic acid;
3-{3-[l-(4-Isopropyl-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{3-[l-(3,4-Difluoro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-7-fluoro-2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
3-{5-Chloro-3-[l-(4-chloro-phenyl)-l-phenyl-meth-(E)-ylidene] -2-oxo-2,3- dihydro-indol- 1 -ylmethylj-benzoic acid;
3-{3-[l-(2-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid;
2- {3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethyl}-thiazole-4-carboxylic acid; 3-{3-[4-Methyl-l-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester;
3-{3-[3,3-Dimethyl-l-phenyl-but-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[2-(4-Chloro-phenyl)-l-phenyl-eth-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[3,3-Dimethyl-l-phenyl-but-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[4-Methyl-l-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid;
3-{3-[l-(4-Chloro-benzyl)-2-methyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Fluoro-phenyl)-eth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyljbenzoic acid;
3-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[2-Methyl-l-phenyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l-ylmethyl}- benzoic acid methyl ester;
3-{3-[l-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-l-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[2-Methyl-l-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene] -2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Cyano-phenyl)-2-hydroxy-2-methyl-prop-(Z)-ylidene] -2-oxo-2,3- dihydro-indol-l-ylmethyl}-benzoic acid methyl ester; 3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid methyl ester;
3-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethylj-benzoic acid;
3-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
6-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l ylmethyl}-pyridine-2-carboxylic acid;
6-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid;
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{3-[l-(4-Cyano-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid;
3-{3-[l-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
6-{3-[l-(4-Fluoro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid;
3-{3-[2-Methyl-l-pyridin-3-yl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-l-cyclohexyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro- indol-1 -ylmethylj-benzoic acid; 3-{3-[2-Methyl-l-(4-trifluoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoic acid;
3-{3-[2-Methyl-l-thiophen-3-yl)-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{5-Chloro-3-[2-methyl-l-(4-trifiuoromethyl-phenyl)-prop-(E)-ylidene]-2-oxo- 2,3-dihydro-indol-l-ylmethyl}-benzoic acid;
3-{3-[l-(4-Acetyl-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
N-(3-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoyl)-methanesulfonamide;
N-(3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoyl)-methanesulfonamide; and
N-(3-{3-[l-(4-Chloro-phenyl)-2,2-dimethyl-prop-(Z)-ylidene]-2-oxo-2,3-dihydro- indol-l-ylmethyl}-benzoyl)-methanesulfonamide.
20. A compound according to anyone of claims 1 to 19 selected from
3-{3-[l-(4-Chloro-phenyl)-l-phenyl-meth-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
3-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethylj-benzoic acid;
6-{3-[l-(4-Chloro-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid; and
6-{3-[l-(4-Cyano-phenyl)-2-methyl-prop-(E)-ylidene]-2-oxo-2,3-dihydro-indol-l- ylmethyl}-pyridine-2-carboxylic acid.
21. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 20 comprising one of the following steps:
(a) the reaction of a compound according to formula (A)
Figure imgf000101_0001
in the presence of R7-X and a copper catalyst;
(b) the reaction of a compound according to formula (B)
Figure imgf000101_0002
in the presence of R8-I and a palladium catalyst;
(c) the reaction of a compound according to formula (C)
Figure imgf000101_0003
in the presence of boron tribromide;
(d) the reaction of a compound according to formula (D)
Figure imgf000102_0001
in the presence of R6-ZnBr and a nickel catalyst;
(e) the reaction of a compound according to formula (E)
Figure imgf000102_0002
in the presence of a base;
(f) the reaction of a compound according to formula (F)
Figure imgf000102_0003
in the presence of R8-B(OH)2 and a palladium catalyst;
(g) the reaction of a compound according to formula (G)
Figure imgf000103_0001
in the presence of MeS02NH2 and a coupling reagent; wherein R1 to R7 are defined as in any one of claims 1 to 18, wherein Ar is phenyl, substituted phenyl, pyridinyl or thiazolyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, wherein R10 is phenyl substituted with one to three substituents independently selected from alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl, wherein R9 is alkyl, wherein R11 is alkyl and wherein X is chloro or bromo.
22. A compound according to any one of claims 1 to 20 for use as therapeutically active substance.
23. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 20 and a therapeutically inert carrier.
24. The use of a compound according to any one of claims 1 to 20 for the preparation of a medicament for the treatment or prophylaxis of obesity, dyslipidemia,
hyperglycemia, type 1 or type 2 diabetes.
25. A compound according to any one of claims 1 to 20, when manufactured according to a process of claim 21.
26. A method for the treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 20.
27. The invention as hereinbefore described.
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WO2016042194A1 (en) * 2014-09-19 2016-03-24 Consejo Superior De Investigaciones Científicas (Csic) Indole derivatives for the prevention and/or treatment of diabetes and associated metabolic disorders
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

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CA2772674A1 (en) 2011-03-24
AU2010297252A1 (en) 2012-02-02
US20130131114A1 (en) 2013-05-23
EP2480530A1 (en) 2012-08-01
WO2011032320A1 (en) 2011-03-24
JP2013505281A (en) 2013-02-14
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US8778973B2 (en) 2014-07-15
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